5-pyridyl-1, 3-azole compounds,  process for producing the same and use there of

ABSTRACT

An optionally N-oxidized compound represented by the formula: 
     
       
         
         
             
             
         
       
     
     wherein R 1  represents hydrogen, hydrocarbon, heterocycle, amino, acyl, R 2  represents an aromatic group, R 3  represents hydrogen, pyridyl, aromatic hydrocarbon, X represents oxygen, optionally oxidized sulfur, Y represents a bond, an oxygen, optionally oxidized sulfur, a group represented by the formula NR 4  (R 4  represents hydrogen, hydrocarbon or acyl) and Z represents a bond or a divalent acyclic hydrocarbon, or a salt thereof has an excellent adenosine A 3  receptor antagonistic activity and is used as an agent for preventing or treating diseases related to an adenosine A 3  receptor. Furthermore, the compound (I) or a salt thereof has p38 MAP kinase inhibitory activity and TNF-α inhibitory activity and is used as an agent for preventing or treating diseases related to p38 MAP kinase and diseases related to TNF-α.

TECHNICAL FIELD

The present invention relates to novel 5-pyridyl-1,3-azole compoundshaving an excellent medical action, particularly an adenosine A₃receptor antagonistic activity, a p38 MAP kinase inhibitory action, aTNF-α production-inhibitory action and the like, a process for producingthe same, a pharmaceutical composition and so on.

BACKGROUND ART

As a subtype of an adenosine receptor, A₁, A_(2a), A_(2b) and A₃ areknown. Adenosine exhibits tracheostenotic action to an asthma patientand, on the other hand, theophylline which is an agent for treatingasthma exhibits adenosine antagonism. In addition, it has been recentlyshown that the activation of A₃ receptor in a rat causes degranulationfrom mast cells (Journal of Biological Chemistry, vol. 268, 16887-16890,1993), and that A₃ receptor is present on eosinophils in peripheralblood and its stimulation activates phospholipase C (PLC) to increasethe intracellular calcium concentration (Blood, vol. 88, 3569-3574,1996).

In addition, cytokines such as TNF-α (tumor necrosis factor-α), IL-1(interleukin-1) and the like are biological substances which areproduced by a variety of cells such as monocyte or macrophage inresponse to the infection and other cellular stress (Koj, A., Biochim.Biophys. Acta, 1317, 84-94 (1996)). Although these cytokines play animportant role in the immune response when they are present at anappropriate amount, it is thought that the overproduction is associatedwith a variety of inflammatory diseases (Dinarello, C. A., Curr. Opin.Immunol., 3, 941-948 (1991)). p38 MAP kinase which was cloned as ahomologue of MAP kinase is associated with the control of production ofthese cytokines and signal transduction system coupled with a receptorand there is a possibility that the inhibition of p38 MAP kinase becomesa drug for treating inflammatory diseases (Stein, B., Anderson, D.,Annual Report in Medicinal Chemistry, edited by Bristol, J. A., AcademicPress, vol. 31, pages 289-298, 1996).

Hitherto, as a compound exhibiting the selective antagonism foradenosine A₃ receptor, xanthine derivatives are reported in GB-A-2288733and WO 95/11681 and the following compounds are reported in Journal ofMedicinal Chemistry, vol. 40, 2596-2608, 1997:

In addition, in WO 97/33879, there are described an adenosine A₃receptor antagonistic agent containing a compound represented by theformula:

wherein R represents hydrogen, chlorine, bromine, fluorine, iodine,hydroxy, C₁₋₄ alkyl, C₁₋₄ alkoxy or C₁₋₄ alkylcarboxy, or a salt thereofand, more specifically, a compound

is described.

In addition, as a compound having a p38 MAP kinase inhibitory action,imidazole derivatives are described in JP-T 7-50317 (WO 93/14081) andoxazole derivatives are described in JP-T 9-505055 (WO 95/13067),respectively.

On the other hand, as thiazole compounds, the following compounds areknown:

1) 1,3-thiazole derivatives represented by the formula:

wherein R¹ represents a cycloalkyl group, a cyclic amino group, an aminogroup optionally having, as a substituent, 1 or 2 lower alkyl, phenyl,acetyl or lower alkoxycarbonylacetyl, an alkyl group optionally having,as a substituent, hydroxyl, carboxyl or lower alkoxycarbonyl, or aphenyl group optionally having, as a substituent, carboxyl,2-carboxylethenyl or 2-carboxy-1-propenyl, R² represents a pyridyl groupoptionally having, as a substituent, lower alkyl, R³ represents a phenylgroup optionally having, as a substituent, lower alkoxy, lower alkyl,hydroxyl, halogen or methylenedioxy, or salts thereof, which haveanalgesic, antipyretic, anti-inflammatory, anti-ulcerative, thromboxaneA₂ (TXA₂) synthesizing enzyme-inhibitory, and plateletcoagulation-inhibitory activities (JP-A 60-58981),2) 1,3-thiazole derivatives represented by the formula:

wherein R¹ represents an alkyl group, an alkenyl group, an aryl group,an aralkyl group, a cycloalkyl group, a heterocyclic group employingcarbon as an attachment point or an amino group optionally havingsubstituents, R² represents a pyridyl group optionally substituted withan alkyl group, R³ represents a phenyl group optionally havingsubstituents, or salts thereof, which have analgesic, antipyretic,anti-inflammatory, anti-ulcerative, TXA² synthesizing enzyme-inhibitory,and platelet coagulation-inhibitory activities (JP-A 61-10580),3) 1,3-thiazole derivatives represented by the formula:

wherein R¹ represents an alkyl group, an alkenyl group, an aryl group,an aralkyl group, a cycloalkyl group, a heterocyclic group employingcarbon as an attachment point or an amino group optionally havingsubstituents, R² represents a pyridyl group optionally substituted withan alkyl group, R³ represents an aryl group optionally havingsubstituents, or salts thereof, which have analgesic, antipyretic,anti-inflammatory, anti-ulcerative, TXA₂ synthesizing enzyme-inhibitory,and platelet coagulation-inhibitory activities (U.S. Pat. No.4,612,321),4) imidazole derivatives represented by the formula:

which have an anti-cancer activity and a cytokine inhibitory activity,more specifically, the following compounds are described (WO 97/12876):

Since an adenosine A₃ antagonist, a p38 MAP kinase inhibiting agent anda TNF-α production-inhibiting agent having the satisfactory activity andeffect, safety, (oral) absorption, (metabolism) stability and the likehave not been found, it is desired the development of the excellentadenosine A₃ receptor antagonist, the p38 MAP kinase-inhibiting agentand the TNF-α production-inhibiting agent as a pharmaceutical which areeffective for preventing or treating adenosine A₃ receptor-relateddiseases, cytokine-mediated diseases and the like.

DISCLOSURE OF THE INVENTION

The present inventors studied variously and, as a result, firstsynthesized novel compounds which may be N-oxidized and which arerepresented by the formula (I):

wherein R¹ represents a hydrogen atom, a hydrocarbon group optionallyhaving substituents, a heterocyclic group optionally havingsubstituents, an amino group optionally having substituents or an acylgroup,R² represents an aromatic group optionally having substituents,R³ represents a hydrogen atom, a pyridyl group optionally havingsubstituents or an aromatic hydrocarbon group optionally havingsubstituents,X represents an oxygen atom or an optionally oxidized sulfur atom,Y represents a bond, an oxygen atom, an optionally oxidized sulfur atomor a group represented by the formula: NR⁴ (wherein R⁴ represents ahydrogen atom, a hydrocarbon group optionally having substituents or anacyl group) andZ represents a bond or a divalent acyclic hydrocarbon group optionallyhaving substituents, or a salt thereof [hereinafter, abbreviated asCompound (I) sometimes], which has a structural characteristics that a5-position of a ring represented by the formula:

wherein X represents an oxygen atom or an optionally oxidized sulfuratom, is substituted with a 4-pyridyl group, and further it has a sidechain having an aromatic group at 2-position of the pyridyl group, foundthat the resulting Compound (I) have unexpectedly excellentpharmaceutical activities such as a selective affinity for an adenosineA₃ receptor and an adenosine A₃ receptor antagonistic activity, a p38MAP kinase inhibitory activity and the like based on the specificchemical structure, and that the compound has also excellent natures inthe physical properties as a pharmaceutical such as stability and thelike and is sufficiently satisfactory as a pharmaceutical, and completedthe present invention based on these findings.

The present invention relates to

(1) an optionally N-oxidized compound represented by the formula:

wherein R¹ represents a hydrogen atom, a hydrocarbon group optionallyhaving substituents, a heterocyclic group optionally havingsubstituents, an amino group optionally having substituents or an acylgroup,R² represents an aromatic group optionally having substituents,R³ represents a hydrogen atom, a pyridyl group optionally havingsubstituents or an aromatic hydrocarbon group optionally havingsubstituents,X represents an oxygen atom or an optionally oxidized sulfur atom,Y represents a bond, an oxygen atom, an optionally oxidized sulfur atomor a group represented by the formula: NR⁴ (wherein. R⁴ represents ahydrogen atom, a hydrocarbon group optionally having substituents or anacyl group) andZ represents a bond or a divalent acyclic hydrocarbon group optionallyhaving substituents, or a salt thereof,(2) the compound according to (1), wherein Z is a divalent acyclichydrocarbon group optionally having substituents,(3) the compound according to (1), which is a compound represented bythe formula:

wherein n represents 0 or 1, and other symbols are as defined in(1), or a salt thereof,(4) the compound according to (1) or (3), wherein R¹ represents(i) a hydrogen atom,(ii) a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group,a C₃₋₆ cycloalkyl group, a C₆₋₁₄ aryl group or a C₇₋₁₆ aralkyl group[these groups may have substituents selected from the group (substituentgroup A) consisting of oxo, halogen atom, C₁₋₃ alkylenedioxy, nitro,cyano, optionally halogenated C₁₋₆ alkyl, optionally halogenated C₂₋₆alkenyl, carboxy C₂₋₆ alkenyl, optionally halogenated C₂₋₆ alkynyl,optionally halogenated C₃₋₆ cycloalkyl, C₆₋₁₄ aryl, optionallyhalogenated C₁₋₈ alkoxy, C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkoxy, hydroxy,C₆₋₁₄ aryloxy, C₇₋₁₆ aralkyloxy, mercapto, optionally halogenated C₁₋₆alkylthio, C₆₋₁₄ arylthio, C₇₋₁₆ aralkylthio, amino, mono-C₁₋₆alkylamino, mono-C₆₋₁₄ arylamino, di-C₁₋₆ alkylamino, di-C₆₋₁₄arylamino, formyl, carboxy, C₁₋₆ alkyl-carbonyl, C₃₋₆cycloalkyl-carbonyl, C₁₋₆ alkoxy-carbonyl, C₆₋₁₄ aryl-carbonyl, C₇₋₁₆aralkyl-carbonyl, C₆₋₁₄ aryloxy-carbonyl, C₇₋₁₆ aralkyloxy-carbonyl, 5or 6 membered heterocyclic carbonyl, carbamoyl, thiocarbamoyl, mono-C₁₋₆alkyl-carbamoyl, di-C₁₋₆ alkyl-carbamoyl, C₆₋₁₄ aryl-carbamoyl, 5 or 6membered heterocyclic carbamoyl, C₁₋₆ alkylsulfonyl, C₆₋₁₄ arylsulfonyl,C₁₋₆ alkylsulfinyl, C₆₋₁₄ arylsulfinyl, formylamino, C₁₋₆alkyl-carbonylamino, C₆₋₁₄ aryl-carbonylamino, C₁₋₆alkoxy-carbonylamino, C₁₋₆ alkylsulfonylamino, C₆₋₁₄ arylsulfonylamino,C₁₋₆ alkyl-carbonyloxy, C₆₋₁₄ aryl-carbonyloxy, C₁₋₆ alkoxy-carbonyloxy,mono-C₁₋₆ alkyl-carbamoyloxy, di-C₁₋₆ alkyl-carbamoyloxy, C₆₋₁₄aryl-carbamoyloxy, nicotinoyloxy, 5 to 7 membered saturated cyclic aminooptionally having 1 to 4 heteroatoms of one or two kinds selected from anitrogen atom, a sulfur atom and an oxygen atom in addition to onenitrogen atom and carbon atoms (this cyclic amino may have substituentsselected from the group consisting of C₁₋₆ alkyl, C₆₋₁₄ aryl, C₁₋₆alkyl-carbonyl, 5 to 10 membered aromatic heterocyclic group and oxo), 5to 10 membered aromatic heterocyclic group containing 1 to 4 heteroatomsof one or two kinds selected from a nitrogen atom, a sulfur atom and anoxygen atom in addition to carbon atoms, sulfo, sulfamoyl, sulfinamoyland sulfinamoyl](iii) a 5 to 14 membered heterocyclic group containing 1 to 4heteroatoms of one or two kinds selected from a nitrogen atom, a sulfuratom and an oxygen atom in addition to carbon atoms optionally havingsubstituents selected from the substituent group A,(iv) an acyl group represented by the formula:

-(C═O)—R⁵,—(C═O)—OR⁵,—(C═O)—NR⁵R⁶,—(C═S)—NHR⁵ or —SO₂—R⁷

(wherein R⁵ represents {circle around (1)} a hydrogen atom, {circlearound (2)} a C₁₋₆ alkyl group, an C₂₋₆ alkenyl group, an C₂₋₆ alkynylgroup, a C₃₋₆ cycloalkyl group, a C₆₋₁₄ aryl group or a C₇₋₁₆ aralkylgroup optionally having substituents selected from the substituent groupA or {circle around (3)} a 5 to 14 membered heterocyclic groupcontaining 1 to 4 heteroatoms of one or two kinds selected from anitrogen atom, a sulfur atom and an oxygen atom in addition to carbonatoms optionally having substituents selected from the substituent groupA, R⁶ represents a hydrogen atom or a C₁₋₆ alkyl group, R⁷ represents{circle around (1)} a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆alkynyl group, a C₃₋₆ cycloalkyl group, a C₆₋₁₄ aryl group or a C₇₋₁₆aralkyl group optionally having substituents selected from thesubstituent group A or {circle around (2)} a 5 to 14 memberedheterocyclic group containing 1 to 4 heteroatoms of one or two kindsselected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms optionally having substituents selected fromthe substituent group A),(v) an amino group (this amino group may have substituents selected fromthe group consisting of {circle around (1)} a C₁₋₆ alkyl group, a C₂₋₆alkenyl group, a C₂₋₆ alkynyl group, a C₃₋₆ cycloalkyl group, a C₆₋₁₄aryl group or a C₇₋₁₆ aralkyl group optionally having substituentsselected from the substituent group A, {circle around (2)} a 5 to 14membered heterocyclic group containing 1 to 4 heteroatoms of one or twokinds selected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms optionally having substituents selected fromthe substituent group A, {circle around (3)} an acyl group as defined inthe (iv), and {circle around (4)} a C₁₋₆ alkylidene group optionallyhaving substituents selected from the substituent group A), or(vi) a 5 to 7 membered non-aromatic cyclic amino group optionallycontaining 1 to 4 heteroatoms of one or two kinds selected from anitrogen atom, a sulfur atom and an oxygen atom in addition to onenitrogen atom and carbon atoms (this cyclic amino may have substituentsselected from the group consisting of C₁₋₆ alkyl, C₆₋₁₄ aryl, C₁₋₆alkyl-carbonyl, 5 to 10 membered aromatic heterocyclic group and oxo);

R² represents {circle around (1)} a C₆₋₁₄ monocyclic or fused polycyclicaromatic hydrocarbon group optionally having substituents selected fromthe substituent group A or {circle around (2)} a 5 to 14 memberedaromatic heterocyclic group containing 1 to 4 heteroatoms of one or twokinds selected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms, optionally having substituents selected fromthe substituent group A;

R³ represents {circle around (1)} a hydrogen atom, {circle around (2)} apyridyl group optionally having substituents selected from thesubstituent group A, or {circle around (3)} C₆₋₁₄ monocyclic or fusedpolycyclic aromatic hydrocarbon group optionally having substituentsselected from the substituent group A;

X represents O, S, SO or SO₂;

Y represents a bond, O, S, SO, SO₂ or a group represented by theformula: NR⁴ (wherein R⁴ represents {circle around (1)} a hydrogen atom,{circle around (2)} a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆alkynyl group, a C₃₋₆ cycloalkyl group, a C₆₋₁₄ aryl group or a C₇₋₁₆aralkyl group optionally having substituents selected from thesubstituent group A or {circle around (3)} an acyl group as defined inthe (iv)),

Z represents a bond, a C₁₋₁₅ alkylene group, a C₂₋₁₆ alkenylene group ora C₂₋₁₆ alkynylene group optionally having substituents selected fromthe substituent group A,

(5) the compound according to (1), wherein R¹ is an amino groupoptionally having substituents,(6) the compound according to (1), wherein R¹ is (i) a C₁₋₆ alkyl group,(ii) a C₆₋₁₄ aryl group optionally substituted with substituentsselected from C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl and halogen atom, or(iii) an amino group optionally having 1 or 2 acyl represented by theformula: —(C═O)—R⁵′ (wherein R⁵′ represents {circle around (1)} a C₁₋₆alkyl group, {circle around (2)} a C₆₋₁₄ aryl group or {circle around(3)} a 5 to 14 membered heterocyclic group containing 1 to 4 heteroatomsof one or two kinds selected from a nitrogen atom, a sulfur atom and anoxygen atom in addition to carbon atoms),(7) the compound according to (1), wherein R¹ is an amino groupoptionally having 1 or 2 acyl group represented by —(C═O)—R⁵″ (whereinR⁵″ represents {circle around (1)} a C₆₋₁₄ aryl group or {circle around(2)} a 5 to 14 membered heterocyclic group containing 1 to 4 heteroatomsof one or two kinds selected from a nitrogen atom, a sulfur atom and anoxygen atom in addition to carbon atoms),(8) the compound according to (1), wherein R² is a C₆₋₁₄ aryl groupoptionally having substituents,(9) the compound according to (1), wherein R² is a C₆₋₁₄ aryl groupoptionally substituted with halogen atom or C₁₋₆ alkoxy, or a 5 to 14membered aromatic heterocyclic group containing 1 to 4 heteroatoms ofone or two kinds selected from a nitrogen atom, a sulfur atom and anoxygen atom in addition to carbon atoms,(10) the compound according to (1), wherein R² is a C₆₋₁₄ aryl group, ora 5 to 14 membered heterocyclic group containing 1 to 4 heteroatoms ofone or two kinds selected from nitrogen atom, a sulfur atom and anoxygen atom in addition to carbon atoms,(11) the compound according to (1), wherein R³ is a C₆₋₁₄ aryl groupoptionally having substituents,(12) the compound according to (1), wherein R³ is a C₆₋₁₄ aryl groupoptionally substituted with one or two C₁₋₆ alkyl or C₁₋₆ alkoxy,(13) the compound according to (1), wherein X is an optionally oxidizedsulfur atom,(14) the compound according to (1), wherein X is a sulfur atom,(15) the compound according to (1), wherein Y is an oxygen atom or agroup represented by the formula: NR⁴ (wherein R⁴ is as defined in (1)),(16) the compound according to (1), wherein Y is an oxygen atom, anoptionally oxidized sulfur atom or a group represented by the formula:NR^(4′) (wherein R^(4′) represents a C₁₋₆ alkyl group),(17) the compound according to (1), wherein Y is O, NH or S,(18) the compound according to (1), wherein Z is a lower alkylene groupoptionally having substituents,(19) the compound according to (1), wherein Z is a bond or a C₁₋₆alkylene group optionally having oxo,(20) the compound according to (1), wherein R¹ is (i) a C₁₋₆ alkylgroup, (ii) a C₆₋₁₄ aryl group optionally substituted with C₁₋₆alkylthio, C₁₋₆ sulfonyl and halogen atom, or (iii) an amino groupoptionally having 1 or 2 acyl group represented by the formula:—(C═O)—R⁵′ (wherein R⁵′ represents {circle around (1)} a C₁₋₆ alkylgroup, {circle around (2)} a C₆₋₁₄ aryl group or {circle around (3)} a 5to 14 membered heterocyclic group containing 1 to 4 heteroatoms of oneor two kinds selected from a nitrogen atom, a sulfur atom and an oxygenatom in addition to carbon atoms;

R² is a C₆₋₁₄ aryl group optionally substituted with halogen atom orC₁₋₆ alkoxy, or a 5 to 14 membered aromatic heterocyclic groupcontaining 1 to 4 heteroatoms of one or two kinds selected from anitrogen atom, a sulfur atom and an oxygen atom in addition to carbonatoms;

R³ is a C₆₋₁₄ aryl group optionally substituted with 1 or 2 C₁₋₆ alkylor C₁₋₆ alkoxy;

X is a sulfur atom;

Y is an oxygen atom, an optionally oxidized sulfur atom or a grouprepresented by the formula: NR⁴′ (wherein R⁴′ represents a C₁₋₆ alkylgroup);

Z is a C₁₋₆ alkylene group optionally having oxo or C₁₋₆ alkyl or abond,

(21) the compound according to (1), wherein R¹ is an amino groupoptionally having 1 or 2 acyl represented by —(C═O)—R⁵″ (wherein R⁵″represents {circle around (1)} a C₆₋₁₄ aryl group or {circle around (2)}a 5 to 14 membered heterocyclic group containing 1 to 4 heteroatoms ofone or two kinds selected from a nitrogen atom, a sulfur atom and anoxygen atom in addition to carbon atoms);

R² is a C₆₋₁₄ aryl group or a 5 to 14 membered aromatic heterocyclicgroup containing 1 to 4 heteroatoms of one or two kinds selected from anitrogen atom, a sulfur atom and an oxygen atom in addition to carbonatoms;

R³ is a C₆₋₁₄ aryl group optionally substituted with 1 or 2 C₁₋₆ alkylor C₁₋₆ alkoxy;

X is a sulfur atom; Y is O, NH or S; Z is a bond or a C₁₋₆ alkylenegroup optionally having oxo,

-   (22)    N-[5-(2-benzoylamino-4-pyridyl)-4-(3,5-dimethylphenyl)-1,3-thiazol-2-yl]acetamide    (Example Compound No. 9),-   N-[5-(2-benzylamino-4-pyridyl)-4-(3,5-dimethylphenyl)-1,3-thiazol-2-yl]acetamide    (Example Compound No. 10),-   N-[4-[4-(4-methoxyphenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide    (Example Compound No. 13),-   N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide    (Example Compound No. 14),-   N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide    (Example Compound No. 15-2),-   N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide    (Example Compound No. 15-3),-   N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide    (Example Compound No. 15-4),-   N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide    (Example Compound No. 15-6),-   N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide    (Example Compound No. 16-1),-   N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide    (Example Compound No. 16-2),-   N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-(4-methoxyphenyl)propionamide    (Example Compound No. 16-3),-   N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-4-phenylbutyramide    (Example Compound No. 16-S),-   N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide    (Example Compound No. 16-7),-   N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide    (Example Compound No. 16-8),-   N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide    (Example Compound No. 16-9),-   N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide    (Example Compound No. 16-10),-   N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide    (Example Compound No. 16-11),-   N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide    (Example Compound No. 16-12),-   N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide    (Example Compound No. 16-15),-   N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide    (Example Compound No. 16-16),-   N-benzyl-N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine    (Example Compound No. 19-2),-   N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine    (Example Compound No. 19-3),-   N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine    (Example Compound No. 19-4),-   N-benzyl-N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]amine    (Example Compound No. 19-5),-   N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine    (Example Compound No. 19-6),-   N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine    (Example Compound No. 19-7),-   N-benzyl-N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine    (Example Compound No. 19-8),-   N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine    (Example Compound No. 19-9),-   N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine    (Example Compound No. 19-10),-   N-benzyl-N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine    (Example Compound No. 19-17),-   N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine    (Example Compound No. 19-18),-   N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine    (Example Compound No. 19-19),-   N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide    (Example Compound No. 20),-   N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide    (Example Compound No. 21-1),-   N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide    (Example Compound No. 21-2),-   N-benzyl-N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine    (Example Compound No. 21-5),-   N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine    (Example Compound No. 21-6),-   N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine    (Example Compound No. 25-1),-   N-(4-fluorobenzyl)-N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine    (Example Compound No. 25-2), or salts thereof,    (23) a prodrug of the compound according to (1),    (24) a process for producing the compound according to (1), which    comprises: reacting a compound represented by the formula:

wherein Hal represents a halogen atom, and other symbols are as definedas (1), or a salt thereof with a compound represented by the formula:

R¹—CSNH₂  (VIII)

wherein R¹ is as defined in (1), or a salt thereof, to obtain a compoundrepresented by the formula:

wherein each symbol is as defined in (1), or a salt thereof, or (ii)reacting a compound represented by the formula:

wherein Hal represents halogen atom, and other symbols are as defined as(1), or a salt thereof with a compound represented by the formula:

R²-Z-YH  (XI)

wherein each symbol is as defined in (1), or a salt thereof, to obtain acompound represented by the formula:

wherein each symbol is as defined in (1), or a salt thereof, or (iii)reacting a compound represented by the formula:

wherein each symbol is as defined in (1), or a salt thereof with acompound represented by the formula:

R²-ZL  (XVIII)

wherein L represents a leaving group, and other symbols are as definedin (1), or a salt thereof, to obtain a compound represented by theformula:

wherein each symbol is as defined in (1), or a salt thereof, or (iv)reacting a compound represented by the formula:

wherein each symbol is as defined in (1), or a salt thereof with peroxyacid, hydrogen peroxide or alkyl hydroperoxide, to obtain a compoundrepresented by the formula:

wherein each symbol is as defined in (1), or a salt thereof,(25) a pharmaceutical composition which comprises the compound accordingto (1) or a prodrug thereof,(26) the composition according to (25), which is an adenosine A₃receptor antagonist,(27) the composition according to (25), which is an agent for preventingor treating adenosine A₃ receptor-related diseases,(28) the composition according to (25), which is an agent for preventingor treating asthma or allergic diseases,(29) the composition according to (25), which is an agent for preventingor treating brain edema, cerebrovascular disease or head trauma,(30) the composition according to (25), which is an agent for inhibitingp38 MAP kinase,(31) the composition according to (25), which is a TNF-αproduction-inhibiting agent,(32) the composition according to (25), which is an agent for preventingor treating cytokine-mediated diseases,(33) the composition according to (25), which is an agent for preventingor treating inflammation, Addison's disease, autoimmune hemolyticanemia, Crohn's disease, psoriasis, rheumatism, spinal trauma, brainedema, multiple sclerosis, Alzheimer's disease, Parkinson's syndrome,amyotrophic lateral sclerosis, diabetes, arthritis, toxemia, Crohn'sdisease, ulcerative colitis, chronic pneumonia, silicosis, pulmonarysarcoidosis, pulmonary tuberculosis, cachexia, arteriosclerosis,Creutzfeldt-Jakob disease, virus infection, atopic dermatitis, systemiclupus erythematosus, AIDS encephalopathy, meningitis, angina, cardiacinfarction, congestive heart failure, hepatitis, transplantation,dialysis hypotension or disseminated intravascular coagulation,(34) a method for antagonizing an adenosine A₃ receptor comprisingadministering an effective amount of an optionally N-oxidized compoundrepresented by the formula:

wherein R¹ represents a hydrogen atom, a hydrocarbon group optionallyhaving substituents, a heterocyclic group optionally havingsubstituents, an amino group optionally having substituents or an acylgroup,R² represents an aromatic group optionally having substituents,R³ represents a hydrogen atom, a pyridyl group optionally havingsubstituents or an aromatic hydrocarbon group optionally havingsubstituents,X represents an oxygen atom or an optionally oxidized sulfur atom,Y represents a bond, an oxygen atom, an optionally oxidized sulfur atomor a group represented by the formula: NR⁴ (wherein R⁴ represents ahydrogen atom, a hydrocarbon group optionally having substituents or anacyl group) andZ represents a bond or a divalent acyclic hydrocarbon group optionallyhaving substituents, or a salt thereof or a prodrug thereof to mammals,(35) a method for inhibiting p38 MAP kinase comprising administering aneffective amount of an optionally N-oxidized compound represented by theformula:

wherein R¹ represents a hydrogen atom, a hydrocarbon group optionallyhaving substituents, a heterocyclic group optionally havingsubstituents, an amino group optionally having substituents or an acylgroup,R² represents an aromatic group optionally having substituents,R³ represents a hydrogen atom, a pyridyl group optionally havingsubstituents or an aromatic hydrocarbon group optionally havingsubstituents,X represents an oxygen atom or an optionally oxidized sulfur atom,Y represents a bond, an oxygen atom, an optionally oxidized sulfur atomor a group represented by the formula: NR⁴ (wherein R⁴ represents ahydrogen atom, a hydrocarbon group optionally having substituents or anacyl group) andZ represents a bond or a divalent acyclic hydrocarbon group optionallyhaving substituents, or a salt thereof or a prodrug thereof to mammals,(36) a method for inhibiting TNF-α production comprising administeringan effective amount of an optionally N-oxidized compound represented bythe formula:

wherein R¹ represents a hydrogen atom, a hydrocarbon group optionallyhaving substituents, a heterocyclic group optionally havingsubstituents, an amino group optionally having substituents or an acylgroup,R² represents an aromatic group optionally having substituents,R³ represents a hydrogen atom, a pyridyl group optionally havingsubstituents or an aromatic hydrocarbon group optionally havingsubstituents,X represents an oxygen atom or an optionally oxidized sulfur atom,Y represents a bond, an oxygen atom, an optionally oxidized sulfur atomor a group represented by the formula: NR⁴ (wherein R⁴ represents ahydrogen atom, a hydrocarbon group optionally having substituents or anacyl group) andZ represents a bond or a divalent acyclic hydrocarbon group optionallyhaving substituents, or a salt thereof or a prodrug thereof to mammals,(37) a method for preventing or treating asthma, allergic diseases,inflammation, Addison's disease, autoimmune hemolytic anemia, Crohn'sdisease, psoriasis, rheumatism, cerebral hemorrhage, cerebralinfarction, head trauma, spinal trauma, brain edema, multiple sclerosis,Alzheimer's disease, Parkinson's syndrome, amyotrophic lateralsclerosis, diabetes, arthritis, toxemia, Crohn's disease, ulcerativecolitis, chronic pneumonia, silicosis, pulmonary sarcoidosis, pulmonarytuberculosis, cachexia, arteriosclerosis, Creutzfeldt-Jakob disease,virus infection, atopic dermatitis, systemic lupus erythematosus, AIDSencephalopathy, meningitis, angina, cardiac infarction, congestive heartfailure, hepatitis, transplantation, dialysis hypotension ordisseminated intravascular coagulation comprising administering aneffective amount of an optionally N-oxidized compound represented by theformula:

wherein R¹ represents a hydrogen atom, a hydrocarbon group optionallyhaving substituents, a heterocyclic group optionally havingsubstituents, an amino group optionally having substituents or an acylgroup,R² represents an aromatic group optionally having substituents,R³ represents a hydrogen atom, a pyridyl group optionally havingsubstituents or an aromatic hydrocarbon group optionally havingsubstituents,X represents an oxygen atom or an optionally oxidized sulfur atom,Y represents a bond, an oxygen atom, an optionally oxidized sulfur atomor a group represented by the formula: NR⁴ (wherein R⁴ represents ahydrogen atom, a hydrocarbon group optionally having substituents or anacyl group) andZ represents a bond or a divalent acyclic hydrocarbon group optionallyhaving substituents, or a salt thereof or a prodrug thereof to mammals,(38) use of an optionally N-oxidized compound represented by theformula:

wherein R¹ represents a hydrogen atom, a hydrocarbon group optionallyhaving substituents, a heterocyclic group optionally havingsubstituents, an amino group optionally having substituents or an acylgroup,R² represents an aromatic group optionally having substituents,R³ represents a hydrogen atom, a pyridyl group optionally havingsubstituents or an aromatic hydrocarbon group optionally havingsubstituents,X represents an oxygen atom or an optionally oxidized sulfur atom,Y represents a bond, an oxygen atom, an optionally oxidized sulfur atomor a group represented by the formula: NR⁴ (wherein R⁴ represents ahydrogen atom, a hydrocarbon group optionally having substituents or anacyl group) andZ represents a bond or a divalent acyclic hydrocarbon group optionallyhaving substituents, or a salt thereof or a prodrug thereof forpreparing an agent for antagonizing an adenosine A₃ receptor,(39) use of an optionally N-oxidized compound represented by theformula:

wherein R¹ represents a hydrogen atom, a hydrocarbon group optionallyhaving substituents, a heterocyclic group optionally havingsubstituents, an amino group optionally having substituents or an acylgroup,R² represents an aromatic group optionally having substituents,R³ represents a hydrogen atom, a pyridyl group optionally havingsubstituents or an aromatic hydrocarbon group optionally havingsubstituents,X represents an oxygen atom or an optionally oxidized sulfur atom,Y represents a bond, an oxygen atom, an optionally oxidized sulfur atomor a group represented by the formula: NR⁴ (wherein R⁴ represents ahydrogen atom, a hydrocarbon group optionally having substituents or anacyl group) andZ represents a bond or a divalent acyclic hydrocarbon group optionallyhaving substituents, or a salt thereof or a prodrug thereof forpreparing an agent for inhibiting p38 MAP kinase,(40) use of an optionally N-oxidized compound represented by theformula:

wherein R¹ represents a hydrogen atom, a hydrocarbon group optionallyhaving substituents, a heterocyclic group optionally havingsubstituents, an amino group optionally having substituents or an acylgroup,R² represents an aromatic group optionally having substituents,R³ represents a hydrogen atom, a pyridyl group optionally havingsubstituents or an aromatic hydrocarbon group optionally havingsubstituents,X represents an oxygen atom or an optionally oxidized sulfur atom,Y represents a bond, an oxygen atom, an optionally oxidized sulfur atomor a group represented by the formula: NR⁴ (wherein R⁴ represents ahydrogen atom, a hydrocarbon group optionally having substituents or anacyl group) andZ represents a bond or a divalent acyclic hydrocarbon group optionallyhaving substituents, or a salt thereof or a prodrug thereof forpreparing an agent for inhibiting a TNF-α production, and(41) use of an optionally N-oxidized compound represented by theformula:

wherein R¹ represents a hydrogen atom, a hydrocarbon group optionallyhaving substituents, a heterocyclic group optionally havingsubstituents, an amino group optionally having substituents or an acylgroup,R² represents an aromatic group optionally having substituents,R³ represents a hydrogen atom, a pyridyl group optionally havingsubstituents or an aromatic hydrocarbon group optionally havingsubstituents,X represents an oxygen atom or an optionally oxidized sulfur atom,Y represents a bond, an oxygen atom, an optionally oxidized sulfur atomor a group represented by the formula: NR⁴ (wherein R⁴ represents ahydrogen atom, a hydrocarbon group optionally having substituents or anacyl group) andZ represents a bond or a divalent acyclic hydrocarbon group optionallyhaving substituents, or a salt thereof or a prodrug thereof forpreparing an agent for preventing or treating asthma, allergic diseases,inflammation, Addison's disease, autoimmune hemolytic anemia, Crohn'sdisease, psoriasis, rheumatism, cerebral hemorrhage, cerebralinfarction, head trauma, spinal trauma, brain edema, multiple sclerosis,Alzheimer's disease, Parkinson's syndrome, amyotrophic lateralsclerosis, diabetes, arthritis, toxemia, Crohn's disease, ulcerativecolitis, chronic pneumonia, silicosis, pulmonary sarcoidosis, pulmonarytuberculosis, cachexia, arteriosclerosis, Creutzfeldt-Jakob disease,virus infection, atopic dermatitis, systemic lupus erythematosus, AIDSencephalopathy, meningitis, angina, cardiac infarction, congestive heartfailure, hepatitis, transplantation, dialysis hypotension ordisseminated intravascular coagulation.

Furthermore, the present invention relates to

(42) the compound according to (1), wherein R¹ is an amino groupoptionally having one or two acyl groups represented by the formula:—(C═O)—R⁵, —(C═O)—OR⁵, —(C═O)—NR⁵R⁶, —(C═S)—NHR⁵ or —SO₂—R⁷ wherein eachsymbols are defined in (4),(43) the compound according to (1), wherein R¹ is a C₁₋₆ alkyl groupoptionally having substituents,(44) the compound according to (1), wherein R¹ is a C₆₋₁₄ aryl groupoptionally having a C₁₋₆ alkylsulfonyl group,(45) the compound according to (7), wherein R⁵″ is a phenyl group or apyridyl group,(46) the compound according to (1), wherein R² is a C₆₋₁₄ aryl groupoptionally having substituents or a 5 to 14 membered aromaticheterocyclic group containing 1 to 4 heteroatoms of one or two kindsselected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms optionally having substituents,(47) the compound according to (1), wherein R² is a phenyl group or apyridyl group, and(48) the compound according to (1), wherein R³ is a phenyl groupoptionally substituted by one or two C₁₋₆ alkyl or C₁₋₆ alkoxy.

BEST MODE TO PRACTICE THE INVENTION

In the aforementioned formula, R¹ represents a hydrogen atom, ahydrocarbon group optionally having substituents, a heterocyclic groupoptionally having substituents, an amino group optionally havingsubstituents or acyl group.

As “acyl group” represented by R¹, for example, there are an acyl grouprepresented by the formula: —(C═O)—R⁵, —(C═O)—OR⁵, —(C═O)—NR⁵R⁶,—(C═S)—NHR⁵ or —SO₂—R⁷ (wherein R⁵ represents a hydrogen atom, ahydrocarbon group optionally having substituents or a heterocyclic groupoptionally having substituents, R⁶ represents a hydrogen atom or a C₁₋₆alkyl, R⁷ represents a hydrocarbon group optionally having substituentsor a heterocyclic group optionally having substituents) and the like.

In the aforementioned formula, as “hydrocarbon group” of “hydrocarbongroup optionally having substituents”, for example, there are an acyclicor cyclic hydrocarbon group (for example, alkyl, alkenyl, alkynyl,cycloalkyl, aryl, aralkyl and the like) and the like. Among them,acyclic or cyclic hydrocarbon groups having carbon number of 1 to 16 arepreferable.

As “alkyl”, for example, C₁₋₆ alkyl (for example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and thelike) is preferable and, in particular, C₁₋₃ alkyl (for example, methyl,ethyl, propyl and isopropyl) and the like are preferable.

As “alkenyl”, for example, C₂₋₆ alkenyl (for example, vinyl, allyl,isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl,1-methyl-2-propenyl, 2-methyl-1-propenyl and the like) and the like arepreferable.

As “alkynyl”, for example, C₂₋₆ alkynyl (for example, ethynyl,propargyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-hexynyl and the like) andthe like are preferable.

As “cycloalkyl”, for example, C₃₋₆ cycloalkyl (for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and the like) and the like arepreferable.

As “aryl”, for example, C₆₋₁₄ aryl (for example, phenyl, 1-naphthyl,2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and thelike) and the like are preferable.

As “aralkyl”, for example, C₇₋₁₆ aralkyl (for example, benzyl,phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl,2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl and thelike) and the like are preferable.

As “substituents” of “hydrocarbon group optionally having substituents”represented by R⁵, for example, there are oxo, halogen atom (forexample, fluorine, chlorine, bromine, iodine and the like), C₁₋₃alkylenedioxy (for example, methylenedioxy, ethylenedioxy and the like),nitro, cyano, optionally halogenated C₁₋₆ alkyl, optionally halogenatedC₂₋₆ alkenyl, carboxy C₂₋₆ alkenyl (for example, 2-carboxylethenyl,2-carboxy-2-methylethenyl and the like), optionally halogenated C₂₋₆alkynyl, optionally halogenated C₃₋₆ cycloalkyl, C₆₋₁₄ aryl (forexample, phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl,4-biphenylyl, 2-anthryl and the like), optionally halogenated C₁₋₈alkoxy, C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkoxy (for example,methoxycarbonylmethyloxy and the like), hydroxy, C₆₋₁₄ aryloxy (forexample, phenyloxy, 1-naphthyloxy, 2-naphthyloxy and the like), C₇₋₁₆aralkyloxy (for example, benzyloxy, phenethyloxy and the like),mercapto, optionally halogenated C₁₋₆ alkylthio, C₆₋₁₄ arylthio (forexample, phenylthio, 1-naphthylthio, 2-naphthylthio and the like), C₇₋₁₆aralkylthio (for example, benzylthio, phenethylthio and the like),amino, mono-C₁₋₆ alkylamino (for example, methylamino, ethylamino andthe like), mono-C₆₋₁₄ arylamino (for example, phenylamino,1-naphthylamino, 2-naphthylamino and the like), di-C₁₋₆ alkylamino (forexample, dimethylamino, diethylamino, ethylmethylamino and the like),di-C₆₋₁₄ arylamino (for example, diphenylamino and the like), formyl,carboxy, C₁₋₆ alkyl-carbonyl (for example, acetyl, propionyl and thelike), C₃₋₆ cycloalkyl-carbonyl (for example, cyclopropylcarbonyl,cyclopentylcarbonyl, cyclohexylcarbonyl and the like), C₁₋₆alkoxy-carbonyl (for example, methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, tert-butoxycarbonyl and the like), C₆₋₁₄ aryl-carbonyl(for example, benzoyl, 1-naphthoyl, 2-naphthoyl and the like), C₇₋₁₆aralkyl-carbonyl (for example, phenylacetyl, 3-phenylpropionyl and thelike), C₆₋₁₄ aryloxy-carbonyl (for example, phenoxycarbonyl and thelike), C₇₋₁₆ aralkyloxy-carbonyl (for example, benzyloxycarbonyl,phenethyloxycarbonyl and the like), 5 or 6 membered heterocycliccarbonyl (for example, nicotinoyl, isonicotinoyl, thenoyl, furoyl,morpholinocarbonyl, thiomorpholinocarbonyl, piperazin-1-ylcarbonyl,pyrrolidin-1-ylcarbonyl and the like), carbamoyl, thiocarbamoyl,mono-C₁₋₆ alkyl-carbamoyl (for example, methylcarbamoyl, ethylcarbamoyland the like), di-C₁₋₆ alkyl-carbamoyl (for example, dimethylcarbamoyl,diethylcarbamoyl, ethylmethylcarbamoyl and the like), C₆₋₁₄aryl-carbamoyl (for example, phenylcarbamoyl, 1-naphthylcarbamoyl,2-naphthylcarbamoyl and the like), 5 or 6 membered heterocycliccarbamoyl (for example, 2-pyridylcarbamoyl, 3-pyridylcarbamoyl,4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl and thelike), C₁₋₆ alkylsulfonyl (for example, methylsulfonyl, ethylsulfonyland the like), C₆₋₁₄ arylsulfonyl (for example, phenylsulfonyl,1-naphthylsulfonyl, 2-naphthylsulfonyl and the like), C₁₋₆ alkylsulfinyl(for example, methylsulfinyl, ethylsulfinyl and the like), C₆₋₁₄arylsulfinyl (for example, phenylsulfinyl, 1-naphthylsulfinyl,2-naphthylsulfinyl and the like), formylamino, C₁₋₆ alkyl-carbonylamino(for example, acetylamino and the like), C₆₋₁₄ aryl-carbonylamino (forexample, benzoylamino, naphthylamino and the like), C₁₋₆alkoxy-carbonylamino (for example, methoxycarbonylamino,ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino and thelike), C₁₋₆ alkylsulfonylamino (for example, methylsulfonylamino,ethylsulfonylamino and the like), C₆₋₁₄ arylsulfonylamino (for example,phenylsulfonylamino, 2-naphthylsulfonylamino, 1-naphthylsulfonylaminoand the like), C₁₋₆ alkyl-carbonyloxy (for example, acetoxy,propionyloxy and the like), C₆₋₁₄ aryl-carbonyloxy (for example,benzoyloxy, naphthylcarbonyloxy and the like), C₁₋₆ alkoxy-carbonyloxy(for example, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy,butoxycarbonyloxy and the like), mono-C₁₋₆ alkyl-carbamoyloxy (forexample, methylcarbamoyloxy, ethylcarbamoyloxy and the like), di-C₁₋₆alkyl-carbamoyloxy (for example, dimethylcarbamoyloxy,diethylcarbamoyloxy and the like), C₆₋₁₄ aryl-carbamoyloxy (for example,phenylcarbamoyloxy, naphthylcarbamoyloxy and the like), nicotinoyloxy, 5to 7 membered saturated cyclic amino optionally having substituents, 5to 10 membered aromatic heterocyclic group (for example, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl,4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl,4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl,2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl,2-benzo[b]furanyl, 3-benzo[b]furanyl and the like), sulfo, sulfamoyl,sulfinamoyl, sulfinamoyl and the like.

The “hydrocarbon group” may have 1 to 5, preferably 1 to 3aforementioned substituents at a substitutable position and, when thenumber of substituents is 2 or more, respective substituents may be thesame or different.

As aforementioned “optionally halogenated C₁₋₆ alkyl”, for example,there are C₁₋₆ alkyl (for example, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like) andthe like optionally having 1 to 5, preferably 1 to 3 halogen atoms (forexample, fluorine, chlorine, bromine, iodine and the like). Examplesthereof are methyl, chloromethyl, difluoromethyl, trichloromethyl,trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl,pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl,4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyland the like.

As the aforementioned “optionally halogenated C₂₋₆ alkenyl”, forexample, there are C₂₋₆ alkenyl (for example, vinyl, propenyl,isopropenyl, 2-buten-1-yl, 4-penten-1-yl, 5-hexen-1-yl) and the likeoptionally having 1 to 5, preferably 1 to 3 halogen atoms (for example,fluorine, chlorine, bromine, iodine and the like).

As the aforementioned “optionally halogenated C₂₋₆ alkynyl”, there areC₂₋₆ alkynyl (for example, 2-butyn-1-yl, 4-pentyn-1-yl, 5-hexyn-1-yl andthe like) and the like optionally having 1 to 5, preferably 1 to 3halogen atoms (for example, fluorine, chlorine, bromine, iodine and thelike).

As the aforementioned “optionally halogenated C₃₋₆ cycloalkyl”, forexample, there are C₃₋₆ cycloalkyl (for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and the like) and the likeoptionally having 1 to 5, preferably 1 to 3 halogen atoms (for example,fluorine, chlorine, bromine, iodine and the like). Examples thereof arecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,4,4-dichlorocyclohexyl, 2,2,3,3-tetrafluorocyclopentyl,4-chlorocyclohexyl and the like.

As the aforementioned “optionally halogenated C₁₋₈ alkoxy”, for example,there are C₁₋₈ alkoxy (for example, methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and thelike) and the like optionally having 1 to 5, preferably 1 to 3 halogenatoms (for example, fluorine, chlorine, bromine, iodine and the like).Examples thereof are methoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy andthe like.

As the aforementioned “optionally halogenated C₁₋₆ alkylthio”, forexample, there are C₁₋₆ alkylthio (for example, methylthio, ethylthio,propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio andthe like) and the like optionally having 1 to 5, preferably 1 to 3halogen atoms (for example, fluorine, chlorine, bromine, iodine and thelike). Examples thereof are methylthio, difluoromethylthio,trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio,4,4,4-trifluorobutylthio, pentylthio, hexylthio and the like.

As “5 to 7 membered saturated cyclic amino” of the aforementioned “5 to7 membered saturated cyclic amino optionally having substituents”, thereare 5 to 7 membered saturated cyclic amino optionally containing 1 to 4heteroatoms of one or two kinds selected from a nitrogen atom, a sulfuratom and an oxygen atom in addition to one nitrogen atom and carbonatoms and examples thereof are pyrrolidin-1-yl, piperidino,piperazin-1-yl, morpholino, thiomorpholino, hexahydroazepin-1-yl and thelike.

As “substituents” of the “5 to 7 membered saturated cyclic aminooptionally having substituents”, for example, there are 1 to 3 C₁₋₆alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl and the like), C₆₋₁₄ aryl (forexample, phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl,4-biphenylyl, 2-anthryl and the like), C₁₋₆ alkyl-carbonyl (for example,acetyl, propionyl and the like), 5 to 10 membered aromatic heterocyclicgroup (for example, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl,1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl,2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl,3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl and the like),oxo and the like.

As “heterocyclic group” of “heterocyclic group optionally havingsubstituents” represented by R⁵, for example, there is a monovalentgroup obtained by removing one arbitrary hydrogen atom from a 5 to 14membered (monocyclic, bicyclic or tricyclic) heterocycle containing 1 to4 heteroatoms of one or two kinds selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms, preferably(i) a 5 to 14 membered (preferably 5 to 10 membered, particularlypreferably 5 to 6 membered) aromatic heterocycle, (ii) a 5 to 10membered (preferably 5 to 6 membered) non-aromatic heterocycle or (iii)a 7 to 10 membered bridged heterocycle.

As the aforementioned “5 to 14 membered (preferably 5 to 10 membered)aromatic heterocycle”, there are an aromatic heterocycle such asthiophene, benzo[b]thiophene, benzo[b]furan, benzimidazole, benzoxazole,benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, pyrrole,imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole,isoindole, 1H-indazole, purine, 4H-quinolizine, isoquinoline, quinoline,phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,carbazole, β-carboline, phenanthridine, acridine, phenazine, thiazole,isothiazole, phenothiazine, isoxazole, furazan, phenoxazine and thelike, and a ring formed by fusing these rings (preferably monocyclic)with 1 or a plurality (preferably 1 to 2) of aromatic rings (forexample, benzene ring and the like).

As the aforementioned “5 to 10 membered non-aromatic heterocycle”, forexample, there are pyrrolidine, imidazoline, pyrazolidine, pyrazoline,piperidine, piperazine, morpholine, thiomorpholine, dioxazole,oxadiazoline, thiadiazoline, triazoline, thiadiazole, dithiazole and thelike.

As the aforementioned “7 to 10 membered bridged heterocycle”, forexample, there are quinuclidine, 7-azabicyclo[2.2.1]heptane and thelike.

The “heterocyclic group” is preferably a 5 to 14 membered (preferably 5to 10 membered) (monocyclic or bicyclic) heterocyclic group containingpreferably 1 to 4 heteroatoms of one or two kinds selected from anitrogen atom, a sulfur atom and an oxygen atom in addition to carbonatoms. More particularly, examples thereof are an aromatic heterocyclicgroup such as 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, S-quinolyl,8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 8-isoquinolyl,pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl,3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-indolyl, 2-indolyl,3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl,2-benzo[b]furanyl, 3-benzo[b]furanyl and the like, and a non-aromaticheterocyclic group such as 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-imidazolinyl, 4-imidazolinyl, 2-pyrazolidinyl,3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidyl, 3-piperidyl,4-piperidyl, 1-piperazinyl, 2-piperazinyl, morpholino, thiomorpholinoand the like.

Among them, for example, a 5 or 6 membered heterocyclic group containing1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and anoxygen atom in addition to carbon atoms is further preferable. Moreparticularly, examples thereof are 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, pyrazinyl, 2-pyrimidinyl,3-pyrrolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-pyrrolidinyl,2-pyrrolidinyl, 3-pyrrolidinyl, 2-imidazolinyl, 4-imidazolinyl,2-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino,2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl,morpholino, thiomorpholino and the like.

As “substituents” of “heterocyclic group optionally havingsubstituents”, for example, there are the same “substituents” assubstituents of “hydrocarbon group optionally having substituents”represented by R⁵.

The “heterocyclic group” may have 1 to 5, preferably 1 to 3aforementioned substituents at a substitutable position and, when thenumber of substituents is 2 or more, respective substituents may be thesame or different.

As “C₁₋₆ alkyl” represented by R⁶, for example, there are methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyland the like.

As “hydrocarbon group optionally having substituents” and “heterocyclicgroup optionally having substituents” represented by R⁷, for example,there are the aforementioned “hydrocarbon group optionally havingsubstituents” and “heterocyclic group optionally having substituents”represented by R⁵, respectively.

As “hydrocarbon group optionally having substituents” and “heterocyclicgroup optionally having substituents” represented by R¹, for example,there are the aforementioned “hydrocarbon group optionally havingsubstituents” and “heterocyclic group optionally having substituents”represented by R⁵, respectively.

As “amino group optionally having substituents” represented by R¹, forexample, there are (1) an amino group optionally having 1 or 2substituents and (2) a cyclic amino group optionally having substituentsand the like.

As “substituents” of “amino group optionally having 1 or 2 substituents”of the aforementioned (1), for example, there are a hydrocarbon groupoptionally having substituents, a heterocyclic group optionally havingsubstituents, an acyl group, an alkylidene group optionally havingsubstituents and the like. As these “hydrocarbon group optionally havingsubstituents” and “heterocyclic group optionally having substituents”,there are the same “hydrocarbon group optionally having substituents”and “heterocyclic group optionally having substituents” as thoserepresented by R⁵ described above, respectively. As the “acyl group”,there is the same “acyl group” as that by represented by R¹ as describedabove.

As “alkylidene group” of “alkylidene group optionally havingsubstituents”, for example, there are a C₁₋₆ alkylidene group (forexample, methylidene, ethylidene, propylidene and the like) and thelike. As “substituents” of “alkylidene group optionally havingsubstituents”, there are 1 to 5, preferably 1 to 3 same substituents as“substituents” of “hydrocarbon group optionally having substituents”represented by R⁵.

When the number of the aforementioned “substituents” of “amino groupoptionally having 1 or 2 substituents” is 2, respective substituents maybe the same or different.

As “cyclic amino group” of “cyclic amino group optionally havingsubstituents” of the aforementioned (2), there are a 5 to 7 memberednon-aromatic cyclic amino group optionally containing 1 to 4 heteroatomsof one or two kinds selected from a nitrogen atom, a sulfur atom and anoxygen atom in addition to one nitrogen atom and carbon atoms. Moreparticularly, examples thereof are pyrrolidin-1-yl, piperidino,piperazin-1-yl, morpholino, thiomorpholino, hexahydroazepin-1-yl,imidazolidin-1-yl, 2,3-dihydro-1H-imidazol-1-yl,tetrahydro-1(2H)-pyrimidinyl, 3,6-dihydro-1(2H)-pyrimidinyl,3,4-dihydro-1(2H)-pyrimidinyl and the like. As “substituents” of “cyclicamino optionally having substituents”, there are 1 to 3 same ones as“substituents” of “5 to 7 membered saturated cyclic amino group” whichwere described in detail as “substituents” of “hydrocarbon groupoptionally having substituents” represented by R⁵.

Examples of the 5 to 7 membered non-aromatic cyclic amino group having 1oxo, there are 2-oxoimidazolidin-1-yl,2-oxo-2,3-dihydro-1H-imidazol-1-yl, 2-oxotetrahydro-1(2H)-pyrimidinyl,2-oxo-3,6-dihydro-1(2H)-pyrimidinyl,2-oxo-3,4-dihydro-1(2H)-pyrimidinyl, 2-oxopyrrolidin-1-yl,2-oxopiperidino, 2-oxopiperazin-1-yl, 3-oxopiperazin-1-yl,2-oxo-2,3,4,5,6,7-hexahydroazepin-1-yl and the like.

As R¹, an amino group optionally having substituents, an aryl groupoptionally having substituents and an alkyl group optionally havingsubstituents and the like are preferable.

As further preferable example of the “amino group optionally havingsubstituents” is an amino group optionally having 1 or 2 acylrepresented by the formula: —(C═O)—R⁵, —(C═O)—OR⁵, —(C═O)—NR⁵R⁶,—(C═S)—NHR⁵ or —SO₂—R⁷ [wherein respective symbols represent the samemeanings as described above]. Particularly preferable example is anamino group optionally having 1 or 2 acyl represented by the formula:—C(C═O)—R⁵ or —(C═O)—NR⁵R⁶ [wherein respective symbols represent thesame meanings as described above].

As the “aryl group optionally having substituents”, for example, thereis preferably a C₆₋₁₄ aryl group (preferably a phenyl group and thelike) optionally having 1 to 5 substituents selected from C₁₋₆alkylthio, C₆₋₁₄ arylthio, C₁₋₆ alkylsulfinyl, C₆₋₁₄ arylsulfinyl, C₁₋₆alkylsulfonyl, C₆₋₁₄ arylsulfonyl and carboxy.

As the “alkyl group optionally having substituents”, for example, a C₁₋₆alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl and the like) optionally substitutedwith 1 to 3 substituents selected from halogen atom, C₁₋₆ alkoxy,hydroxy, carboxy and C₁₋₆ alkoxy-carbonyl and the like are preferable,and particularly C₁₋₃ alkyl group such as methyl, ethyl and the like ispreferable.

Among them, as R¹, (i) C₁₋₆ alkyl group (for example, C₁₋₄ alkyl groupsuch as methyl, ethyl, propyl, butyl), (ii) a C₆₋₁₄ aryl group (forexample, a phenyl group) optionally substituted with substituentsselected from C₁₋₆ alkylthio (for example, methylthio), C₁₋₆alkylsulfonyl (for example, methylsulfonyl) and halogen atom (forexample, chlorine atom, fluorine atom) or (iii) an amino groupoptionally having 1 or 2 acyl represented by the formula: —(C═O)—R⁵′(wherein R⁵′ represents {circle around (1)} a C₁₋₆ alkyl group (forexample, C₁₋₃ alkyl group such as methyl), {circle around (2)} a C₆₋₁₄aryl group (for example, a phenyl group) or {circle around (3)} a 5 to14 membered heterocyclic group containing 1 to 4 heteroatoms of one ortwo kinds selected from a nitrogen atom, a sulfur atom and an oxygenatom in addition to carbon atoms (for example, a 5 to 6 memberedheterocyclic group containing 1 to 2 heteroatoms selected from anitrogen atom, a sulfur atom and an oxygen atom in addition to carbonatoms such as pyridyl group) are preferable. As R⁵′ and R⁵″, a phenylgroup or a pyridyl group is suitable.

In the aforementioned formula, R² represents an aromatic groupoptionally having substituents.

As “aromatic group” of “aromatic group optionally having substituents”represented by R², for example, there are an aromatic hydrocarbon group,an aromatic heterocyclic group and the like.

As the “aromatic hydrocarbon group”, examples thereof include a C₆₋₁₄monocyclic or fused polycyclic (bicyclic or tricyclic) aromatichydrocarbon group, etc. As examples, there are a C₆₋₁₄ aryl group andthe like such as phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl,3-biphenylyl, 4-biphenylyl, 2-anthryl and the like and, furtherpreferably, a C₆₋₁₀ aryl group and the like (for example, phenyl,1-naphthyl, 2-naphthyl and the like, preferably phenyl and the like).

As the “aromatic heterocyclic group”, there is a monovalent groupobtained by removing one arbitrary hydrogen atom from 5 to 14 membered(preferably 5 to 10 membered) aromatic heterocycle containing 1 to 4heteroatoms of one or two kinds selected from nitrogen atom, sulfur atomand oxygen atom in addition to carbon atoms.

As the aforementioned “5 to 14 membered (preferably 5 to 10 membered)aromatic heterocycle”, for example, there are an aromatic heterocyclesuch as thiophene, benzo[b]thiophene, benzo[b]furan, benzimidazole,benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene,furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine,pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolizine,isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline,quinazoline, cinnoline, carbazole, β-carboline, phenanthridine,acridine, phenazine, thiazole, isothiazole, phenothiazine, isoxazole,furazan, phenoxazine and the like, and a ring formed by fusing theserings (preferably monocycle) with 1 or a plurality of (preferably 1 or2) aromatic rings (for example, benzene ring and the like).

As the “aromatic heterocyclic group”, there are preferably a 5 to 14membered (preferably 5 to 10 membered) (monocyclic or bicyclic) aromaticheterocyclic group containing preferably 1 to 4 heteroatoms of one ortwo kinds selected from a nitrogen atom, a sulfur atom and an oxygenatom in addition to carbon atoms and the like and, more particularly,there are an aromatic heterocyclic group such as 2-thienyl, 3-thienyl,2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl,3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl,3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, pyrazinyl, 2-pyrimidinyl,4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl,3-isoxazolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl,2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl,3-benzo[b]furanyl and the like.

As “substituents” of “aromatic group optionally having substituents”,there are 1 to 5, preferably 1 to 3 same substituents as “substituents”of “hydrocarbon group optionally having substituents” represented by R⁵.When the number of substituents is 2 or more, respective substituentsmay be the same or different.

As R², (1) a C₆₋₁₄ aryl group optionally having substituents and (2) a 5to 14 membered aromatic heterocyclic group containing 1 to 4 heteroatomsof one or two kinds selected from a nitrogen atom, a sulfur atom and anoxygen atom in addition to carbon atoms are preferable and, among them,(1) a C₆₋₁₄ aryl group (for example, phenyl group, naphthyl group)optionally substituted with halogen atom (for example, chlorine atom,fluorine atom) or C₁₋₆ alkoxy (for example, methoxy), (2) a 5 to 14membered aromatic heterocyclic group containing 1 to 4 heteroatoms ofone or two kinds selected from a nitrogen atom, a sulfur atom and anoxygen atom in addition to carbon atoms (for example, a 5 to 6 memberedaromatic heterocyclic group containing 1 to 2 heteroatoms selected froma nitrogen atom, a sulfur atom and an oxygen atom in addition to carbonatoms such as pyridyl group, thienyl group) and the like are preferableand, in particular, a phenyl group, a pyridyl group and the like aresuitable.

In the aforementioned formula, R³ represents a hydrogen atom, a pyridylgroup optionally having substituents or an aromatic hydrocarbon groupoptionally having substituents.

As “substituents” of “pyridyl group optionally having substituents”represented by R³, there are the same substituents as “substituents” of“hydrocarbon group optionally having substituents” represented by R⁵.

The “pyridyl group” may, for example, have 1 to 5, preferably 1 to 3aforementioned substituents at substitutable positions and, when thenumber of substituents is 2 or more, respective substituents may be thesame or different. In addition, an intracyclic nitrogen atom may beN-oxidized.

As “aromatic hydrocarbon group” of “aromatic hydrocarbon groupoptionally having substituents” represented by R³, there is the samearomatic hydrocarbon group as “aromatic hydrocarbon group” of “aromatichydrocarbon group optionally having substituents” represented by R² and,preferably, there are a C₆₋₁₄ aryl group and the like such as phenyl,1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl,2-anthryl and the like and, further preferably, a C₆₋₁₀ aryl group andthe like (for example, phenyl, 1-naphthyl, 2-naphthyl and the like,preferably phenyl and the like) and the like. As “substituents” of“aromatic hydrocarbon group optionally having substituents” representedby R³, there are the same substituents as substituents of “aromaticgroup optionally having substituents” represented by R²

As R³, a C₆₋₁₄ aryl group optionally having substituents is preferableand, among them, a C₆₋₁₄ aryl group optionally substituted with 1 or 2C₁₋₆ alkyl (for example, methyl, ethyl and the like) or C₁₋₆ alkoxy (forexample, methoxy, ethoxy and the like) is preferable and, in particular,a phenyl group optionally substituted with 1 or 2 C₁₋₆ alkyl or C₁₋₆alkoxy (for example, 3-methoxyphenyl, 2-methylphenyl, 2,4-dimethylphenyland the like) is suitable.

In the aforementioned formula, X represents an oxygen atom or anoptionally oxidized sulfur atom.

As “optionally oxidized sulfur atom” represented by X, there are S, SOand SO₂.

As X, there is preferably an optionally oxidized sulfur atom. Furtherpreferably, it is S.

In the aforementioned formula, Y represents a bond, an oxygen atom, anoptionally oxidized sulfur atom or the formula NR⁴ (wherein R⁴represents a hydrogen atom, a hydrocarbon group optionally havingsubstituents or an acyl group).

As “optionally oxidized sulfur atom” represented by Y, there are S, SOand SO₂.

As “hydrocarbon group optionally having substituents” represented by R⁴,for example, there is the same group as “hydrocarbon group optionallyhaving substituents” represented by R⁵. Among them, a C₁₋₆ alkyl groupsuch as methyl, ethyl and the like and, in particular, a C₁₋₃ alkylgroup such as methyl and the like is preferable.

As “acyl group” represented by R⁴, there is the same group as “acylgroup” represented by R¹.

As Y, an oxygen atom, an optionally oxidized sulfur atom, a grouprepresented by the formula NR⁴ (wherein R⁴ represents the same meaningas that described above) and the like are preferable and, among them, anoxygen atom, an optionally oxidized sulfur atom, a group represented bythe formula NR⁴′ (R⁴′ represents a hydrogen group or a C₁₋₆ alkyl group)and the like are preferable and, further, an oxygen atom, S, SO₂, NH,N(CH₃) and the like are preferable and, in particular, O or NH issuitable.

In the aforementioned formula, Z represents a bond or a divalent acyclichydrocarbon group optionally having substituents.

As “divalent acyclic hydrocarbon group” of “divalent acyclic hydrocarbongroup optionally having substituents”, for example, there are a C₁₋₁₅alkylene group (for example, methylene, ethylene, propylene, butylene,pentamethylene, hexamethylene, heptamethylene, octamethylene and thelike, preferably a C₁₋₆ alkylene group and the like), a C₂₋₁₆ alkenylenegroup (for example, vinylene, propylene, 1-butenylene, 2-butenylene,1-pentenylene, 2-pentenylene, 3-pentenylene and the like), a C₂₋₁₆alkynylene group (ethynylene, propynylene, 1-butenylene, 2-butenylene,1-pentenylene, 2-pentenylene, 3-pentenylene and the like) and the like,preferably, a C₁₋₁₅ alkylene group, particularly preferably, a C₁₋₆alkylene group and the like. As “substituents” of “divalent acyclichydrocarbon group optionally having substituents” represented by Z, forexample, there are the same substituents as “substituents” of“hydrocarbon group optionally having substituents” represented by R⁵.

As Z, a lower alkylene group optionally having C₁₋₃ alkyl (for example,methyl), oxo and the like (for example, a C₁₋₆ alkylene group such asmethylene, ethylene, propylene and the like, in particular, a C₁₋₃alkylene group) is preferable and, among them, a C₁₋₆ alkylene groupoptionally having oxo (for example, a C₁₋₃ alkylene group such asmethylene, ethylene, propylene, in particular, methylene) is suitable.

More particularly, as Z, —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —CO—, —CH₂CO—,—(CH₂)₂CO—, —CH(CH₃)— and the like are used and, in particular, —CH₂—,—CO— and the like are suitable.

A nitrogen atom in Compound (I) may be N-oxidized. For example, anitrogen atom which is a constituent atom of 4-pyridyl group as asubstituent at 5-position of a ring represented by the formula:

wherein a symbol in the formula represents the same meaning as thatdescribed above, may be N-oxidized. As Compound (I), for example, acompound represented by the formula:

wherein n represents 0 or 1, and other symbols represents the samemeanings as those described above, or salts thereof are preferable.

As Compound (I), compounds shown by the following (A) to (F) arepreferably used.

(A) Compound (I) wherein R¹ is an amino group optionally havingsubstituents, R² is a C₆₋₁₄ aryl group optionally having substituents,R³ is a C₆₋₁₄ aryl group optionally having substituents, X is a sulfuratom, Y is an oxygen atom or a group represented by the formula NR⁴(wherein R⁴ represents the same meaning as that described above) or(and) Z is a lower alkylene group optionally having substituents.(B) Compound (I) wherein R¹ is (i) a C₁₋₆ alkyl group (for example, aC₁₋₄ alkyl group such as methyl, ethyl, propyl, butyl and the like),(ii) a C₆₋₁₄ aryl group (for example, a phenyl group) optionallysubstituted with substituents selected from C₁₋₆ alkylthio (for example,methylthio), C₁₋₆ alkylsulfonyl (for example, methylsulfonyl) andhalogen atom (for example, chlorine atom, fluorine atom), or(iii) an amino group optionally having 1 or 2 acyl represented by theformula: —(C═O)—R⁵′ [wherein R⁵′ represents {circle around (1)} a C₁₋₆alkyl group (for example, C₁₋₃ alkyl group such as methyl and the like),{circle around (2)} a C₆₋₁₄ aryl group (for example, a phenyl group) or{circle around (3)} a 5 to 14 membered heterocyclic group containing 1to 4 heteroatoms of one or two kinds selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms (for example,a 5 to 6 membered heterocyclic group containing 1 to 2 heteroatomsselected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms such as a pyridyl group);

R² is a C₆₋₁₄ aryl group (for example, a phenyl group, a naphthyl group)optionally substituents with halogen atom (for example, chlorine atom,fluorine atom) or C₁₋₆ alkoxy (for example, methoxy), or a 5 to 14membered aromatic heterocyclic group containing 1 to 4 heteroatoms ofone or two kinds selected from a nitrogen atom, a sulfur atom and anoxygen atom in addition to carbon atoms (for example, a 5 to 6 memberedaromatic heterocyclic group containing 1 to 2 heteroatoms selected froma nitrogen atom, a sulfur atom and an oxygen atom in addition to carbonatoms such as a pyridyl group, a thienyl group and the like);

R³ is a C₆₋₁₄ aryl group (particularly, a phenyl group) optionallysubstituted with 1 or 2 C₁₋₆ alkyl (for example, methyl) or C₁₋₆ alkoxy(for example, methoxy);X is a sulfur atom;Y is an oxygen atom, an optionally oxidized sulfur atom or a grouprepresented by the formula NR⁴′ (R⁴′ is a hydrogen atom or a C₁₋₆ alkylgroup) (in particular, an oxygen atom, S, SO₂, NH, N(CH₃) and the like);

Z is a C₁₋₆ alkylene group (in particular, a C₁₋₃ alkylene group)optionally having oxo or C₁₋₆ alkyl (for example, C₁₋₃ alkyl such asmethyl) or a bond.

(C) Compound (I) wherein R¹ is an amino group optionally having 1 or 2acyl represented by the formula —(C═O)—R⁵″ (wherein R⁵″ represents{circle around (1)} a C₆₋₁₄ aryl group (for example, phenyl group) or{circle around (2)} a 5 to 14 membered heterocyclic group containing 1to 4 heteroatoms of one or two kinds selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms (for example,a 5 to 6 membered heterocyclic group containing 1 to 2 heteroatomsselected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms such as a pyridyl group);

R² is a C₆₋₁₄ aryl group (for example, a phenyl group) or a 5 to 14membered aromatic heterocyclic group containing 1 to 4 heteroatoms ofone or two kinds selected from a nitrogen atom, a sulfur atom and anoxygen atom in addition to carbon atoms (for example, a 5 to 6 memberedaromatic heterocyclic group containing 1 to 2 heteroatoms selected froma nitrogen atom, a sulfur atom and an oxygen atom in addition to carbonatoms such as a pyridyl group);

R³ is a C₆₋₁₄ aryl group (in particular, a phenyl group) optionallysubstituted with 1 or 2 C₁₋₆ alkyl (for example, methyl) or C₁₋₆ alkoxy(for example, methoxy);

X is a sulfur atom;

Y is O, NH or S;

Z is a bond or a C₁₋₆ alkylene group (in particular, a C₁₋₃ alkylenegroup optionally having oxo, such as methylene, ethylene and the like)optionally having oxo.

(D) Compound (I) prepared in Examples 1-79.

-   (E)    [4-(3,5-dimethylphenyl)-5-(2-phenylmethyloxy-4-pyridyl)-1,3-thiazol-2-yl]amine    (Example Compound No. 1),-   N-[4-[2-benzoylamino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide    (Example Compound No. 2),-   N-[4-(4-methoxyphenyl)-5-[2-[(3-pyridylcarbonylamino)]-4-pyridyl]-1,3-thiazol-2-yl]nicotinamide    (Example Compound No. 3),-   N-[4-[2-amino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide    (Example Compound No. 4),-   N-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide    (Example Compound No. 5),-   N-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzylamine    (Example Compound No. 6),-   N-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide    hydrochloride (Example Compound No. 7),-   N-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzylamine    dihydrochloride (Example Compound No. 8).-   (F)    N-[5-[2-benzoylamino-4-pyridyl)-4-(3,5-dimethylphenyl)-1,3-thiazol-2-yl]acetamide    (Example Compound No. 9),-   N-[5-(2-benzylamino-4-pyridyl)-4-(3,5-dimethylphenyl)-1,3-thiazol-2-yl]acetamide    (Example Compound No. 10),-   N-[4-[4-(4-methoxyphenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide    (Example Compound No. 13),-   N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide    (Example Compound No. 14),-   N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide    (Example Compound No. 15-2),-   N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide    (Example Compound No. 15-3),-   N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide    (Example Compound No. 15-4),-   N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide    (Example Compound No. 15-6),-   N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide    (Example Compound No. 16-1),-   N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide    (Example Compound No. 16-2),-   N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-(4-methoxyphenyl)propionamide    (Example Compound No. 16-3),-   N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-4-phenylbutyramide    (Example Compound No. 16-5),-   N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide    (Example Compound No. 16-7),-   N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide    (Example Compound No. 16-8),-   N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide    (Example Compound No. 16-9),-   N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide    (Example Compound No. 16-10),-   N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide    (Example Compound No. 16-11),-   N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide    (Example Compound No. 16-12),-   N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide    (Example Compound No. 16-15),-   N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide    (Example Compound No. 16-16),-   N-benzyl-N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine    (Example Compound No. 19-2),-   N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine    (Example Compound No. 19-3),-   N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine    (Example Compound No. 19-4),-   N-benzyl-N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]amine    (Example Compound No. 19-5),-   N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine    (Example Compound No. 19-6),-   N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine    (Example Compound No. 19-7),-   N-benzyl-N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine    (Example Compound No. 19-8),-   N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine.    (Example Compound No. 19-9),-   N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine    (Example Compound No. 19-10),-   N-benzyl-N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine    (Example Compound No. 19-17),-   N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine    (Example Compound No. 19-18),-   N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine    (Example Compound No. 19-19),-   N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide    (Example Compound No. 20),-   N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide    (Example Compound No. 21-1),-   N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide    (Example Compound No. 21-2),-   N-benzyl-N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine    (Example Compound No. 21-5),-   N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine    (Example Compound No. 21-6),-   N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine    (Example Compound No. 25-1),-   N-(4-fluorobenzyl)-N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine    (Example Compound No. 25-2).

As a salt of Compound (I), for example, there are a metal salt, ammoniumsalt, a salt with an organic base, salt with an inorganic acid, a saltwith an organic acid, a salt with basic or acidic amino acid and thelike. As a suitable metal salt, there are alkali metal salt such assodium salt, potassium salt and the like; alkaline earth metal salt suchas calcium salt, magnesium salt, barium salt and the like; aluminum saltand the like. As a suitable example of a salt with an organic base, forexample, there are salts with trimethylamine, triethylamine, pyridine,picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine,cyclohexylamine, dicyclohexylamine, N,N′-dibenzylethylenediamine and thelike. As a suitable example of a salt with an inorganic acid, forexample, there are salts with hydrochloric acid, hydrobromic acid,nitric acid, sulfuric acid, phosphoric acid and the like. As a suitableexample of a salt with an organic acid, for example, there are saltswith formic acid, acetic acid, trifluoroacetic acid, phthalic acid,fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid,succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid and the like. As a suitable example of a saltwith a basic amino acid, for example, there are salts with alginine,lysine, ornithine and the like. As a suitable example of a salt with anacidic amino acid, for example, there are salts with aspartic acid,glutamic acid and the like.

Among them, pharmaceutically acceptable salts are preferable. Forexample, when a compound has an acidic functional group therein, thereare inorganic salts such as alkali metal salt (for example, sodium salt,potassium salt and the like), alkaline earth metal salt (for example,calcium salt, magnesium salt, barium salt and the like), ammonium saltsand the like and, when a compound has a basic functional group therein,there are salts with inorganic acids such as hydrochloric acid,hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and thelike, and salts with organic acids such as acetic acid, phthalic acid,fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid,succinic acid, methanesulfonic acid, p-toluenesulfonic acid and thelike.

A process for producing Compound (I) will be described below. Compound(Ia), (Ib), (Ic) or (Id) is a compound included in Compound (I).

Compound (I) is obtained by a method shown by the following reactionformulas 1, 2, 4 and 5 or a similar method to that.

Respective symbols in compounds in the following reaction formulas 1, 2,4 and 5 have the same meanings as those described above. Compounds inthe reaction formulas include salts thereof and, as the salts, forexample, there are the same as those of Compound (I).

Compounds (II), (III), (V), (VIII), (XI), (XII), (XVII), (XVIII), (XIX),(XX), (XXI), (XXII), (XXVI) and (XXVII) can be used as they are whenthey are commercially available or can be prepared by a method known perse or according to the similar method to this.

Compound (IV) can be obtained by condensing Compound (II) and Compound(III) in the presence of a base.

An amount of Compound (III) to be used is about 0.5 to about 3 moles,preferably about 0.8 to about 2 moles relative to 1 mole of Compound(II).

An amount of a base to be used is about 1 to about 30 moles, preferablyabout 1 to about 10 moles relative to 1 mole of Compound (II).

As the “base”, for example, there are a basic salt such as sodiumcarbonate, potassium carbonate, cesium carbonate, sodium acetate and thelike, an inorganic base such as sodium hydroxide, potassium hydroxideand the like, an aromatic amine such as pyridine, lutidine and the like,a tertiary amine such as triethylamine, tripropylamine, tributylamine,cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline,N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and thelike, an alkali metal hydride such as sodium hydride, potassium hydrideand the like, a metal amide such as sodium amide, lithiumdiisopropylamide, lithium hexamethyldisilazide and the like, a metalalkoxide such as sodium methoxide, sodium ethoxide, potassiumtert-butoxide and the like.

It is advantageous that this reaction is conducted without a solvent orin the presence of an inert solvent. Although the solvent is notparticularly limited as long as the reaction proceeds, for example,halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons,ethers, amides, alcohols, water or a mixture of two or more of them areused.

A reaction temperature is usually about −5 to about 200° C., preferablyabout 5 to about 150° C. A reaction time is usually about 5 minutes toabout 72 hours, preferably about 0.5 to about 20 hours.

Although the reaction product can be used as the reaction solutionitself or as a crude product in the next step, it can be isolated fromthe reaction mixture according to the conventional method and can beeasily purified by a separating means such as recrystallization,distillation, chromatography and the like.

Compound (VI) can be obtained by treating Compound (IV) with a base andcondensing the obtained compound with Compound (V).

In Compound (V), L represents a leaving group. As “leaving group”denoted by L, for example, there are {circle around (1)} C₁₋₆ alkoxy(for example, methoxy, ethoxy and the like), {circle around (2)} di-C₁₋₆alkylamino (for example, dimethylamino, diethylamino and the like),{circle around (3)} N—C₆₋₁₀ aryl-N—C₁₋₆ alkylamino (for example,N-phenyl-N-methylamino and the like), {circle around (4)} 3 to 7membered cyclic amino (for example, pyrrolidino, morpholino,methylaziridin-1-yl and the like) optionally substituted with C₆₋₁₀ aryland (or) C₁₋₆ alkyl, {circle around (5)} N—C₁₋₆ alkyl-N—C₁₋₆ alkoxyamino(N-methoxy-N-methylamino and the like) and the like. Further, as“leaving group” denoted by L, for example, there are hydroxy, halogenatom (for example, fluorine, chlorine, bromine, iodine and the like),optionally halogenated C₁₋₅ alkylsulfonyloxy (for example,methanesulfonyloxy, ethanesulfonyloxy, trichloromethanesulfonyloxy andthe like), C₆₋₁₀ arylsulfonyloxy optionally having substituents and thelike. As “C₆₋₁₀ arylsulfonyloxy optionally having substituents”, forexample, there are C₆₋₁₀ arylsulfonyloxy (for example,phenylsulfonyloxy, naphthylsulfonyloxy and the like) optionally having 1to 3 substituents selected from C₁₋₆ alkyl, C₁₋₆ alkoxy and nitro.Examples thereof are benzenesulfonyloxy, m-nitrobenzenesulfonyloxy,p-toluenesulfonyloxy and the like.

An amount of a base to be used is about 0.8 to about 3 moles, preferablyabout 1 to about 1.2 moles relative to 1 mole of Compound (IV).

As the “base”, for example, metal amides such as sodium amide, lithiumdiisopropylamide, lithium hexamethyldisilazide and the like are used.

It is advantageous that this reaction is conducted without a solvent orin the presence of an inert solvent for a reaction. The solvent is notparticularly limited as long as a reaction proceeds but, for example,aliphatic hydrocarbons, aromatic hydrocarbons, ethers or a mixture oftwo or more of them and the like are used.

A reaction temperature is usually about −78 to about 60° C., preferablyabout −78 to about 20° C. A reaction time is usually about 5 minutes toabout 24 hours, preferably about 0.5 to about 3 hours.

Although a product can be used as the reaction solution itself or as acrude product in the next reaction, it can be isolated from the reactionmixture by the conventional method, and can be easily purified by aseparating means such as recrystallization, distillation, chromatographyand the like.

Compound (VII) can be obtained by treating Compound (VI) with halogensor a metal halide. This reaction is performed in the presence of a baseor a basic salt if desired.

An amount of halogens or a metal halide to be used is about 1 to about 5moles, preferably about 1 to about 2 moles relative to 1 mole ofCompound (VI).

As the “halogens”, there are bromine, chlorine, iodine and the like.

As the “metal halide”, there are copper halide such as copper (II)bromide, copper (II) chloride and the like.

An amount of a base to be used is about 1 to about 30 moles, preferablyabout 1 to about 10 moles relative to 1 mole of Compound (VI).

As the “base”, for example, there are inorganic bases such as sodiumhydroxide, potassium hydroxide, lithium hydroxide and the like, basicsalts such as sodium carbonate, potassium carbonate, cesium carbonate,sodium hydrogencarbonate and the like, aromatic amines such as pyridine,lutidine and the like, tertiary amines such as triethylamine,tripropylamine, tributylamine, cyclohexyldimethylamine,4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylpyrrolidine, N-methylmorpholine and the like.

It is advantageous that this reaction is performed without a solvent orin the presence of an inert solvent for a reaction. The solvent is notparticularly limited as long as a reaction proceeds but, for example,ethers, esters, aromatic hydrocarbons, aliphatic hydrocarbons, amides,halogenated hydrocarbons, nitrites, sulfoxides, organic acids, aromaticamines or a mixture of two or more of them and the like are used.

A reaction temperature is about −20 to about 150° C., preferably about 0to about 100° C. A reaction time is usually about 5 minutes to about 24hours, preferably about 10 minutes to about 5 hours.

Although a product can be used as the reaction solution itself or as acrude product in the next reaction, it can be isolated from the reactionmixture by the conventional method, and can be easily purified by aseparating means such as recrystallization, distillation, chromatographyand the like.

Compound (Ia) can be obtained by condensing Compound (VII) with Compound(VIII). This reaction is performed in the presence of a base if desired.

In Compound (VII), Hal represents halogens.

When Compound (VIII) is commercially available, it can be used as it is,or can be obtained by the method known per se or a method according tothe known method or further a method shown in the reaction formula 3.

An amount of Compound (VIII) to be used is about 0.5 to about 3 moles,preferably about 0.8 to about 2 moles relative to 1 mole of Compound(VII).

An amount of a base to be used is about 1 to about 30 moles, preferablyabout 1 to about 10 moles relative to 1 mole of Compound (VII).

As the “base”, for example, there are alkali metal such as sodiumhydroxide, potassium hydroxide, lithium hydroxide and the like, basicsalts such as sodium carbonate, potassium carbonate, cesium carbonate,sodium hydrogencarbonate and the like, aromatic amines such as pyridine,lutidine and the like, tertiary amines such as triethylamine,tripropylamine, tributylamine, cyclohexyldimethylamine,4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylpyrrolidine, N-methylmorpholine and the like.

It is advantageous that this reaction is performed without a solvent orin the presence of an inert solvent for a reaction. The solvent is notparticularly limited as long as a reaction proceeds but, for example,halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons,ethers, amides, alcohols, nitrites or a mixture of two or more of themand the like are used.

A reaction temperature is about −5 to about 200° C., preferably about 5to about 150° C. A reaction time is usually about 5 minutes to about 72hours, preferably about 0.5 to about 30 hours.

Although a product can be used as the reaction solution itself or as acrude product in the next reaction, it can be isolated from the reactionmixture by the conventional method, and can be easily purified by aseparating means such as recrystallization, distillation, chromatographyand the like.

Compound (IX) can be obtained by treating Compound (Ia) with an acid.

An amount of an acid to be used is about 1 to about 100 moles,preferably about 1 to about 30 moles relative to 1 mole of Compound(Ia).

As the “acid”, for example, there are mineral acids such as hydrochloricacid, hydrobromic acid, sulfuric acid and the like, organic acids suchas acetic acid, propionic acid, trifluoroacetic acid and the like.

This reaction is performed in the presence of an inert solvent for areaction. The solvent is not particularly limited as long as a reactionproceeds but, for example, water, a mixture of water and amides, amixture of water and alcohols and the like are used.

A reaction temperature is usually about 20 to about 200° C., preferablyabout 60 to about 150° C. A reaction time is usually about 30 minutes toabout 72 hours, preferably about 1 to about 30 hours.

Although a product can be used as the reaction solution itself or as acrude product in the next reaction, it can be isolated from the reactionmixture by the conventional method, and can be easily purified by aseparating means such as recrystallization, distillation, chromatographyand the like.

Compound (X) is obtained by treating Compound (IX) with a halogenatingagent.

An amount of a halogenating agent to be used is about 1 to about 10moles, preferably about 1 to about 5 moles relative to 1 mole ofCompound (IX).

As the “halogenating agent”, there are thionyl chloride, phosphoruspentachloride, phosphorus oxychloride and the like.

It is advantageous that this reaction is performed without a solvent orin the presence of an inert solvent for a reaction. The solvent is notparticularly limited as long as a reaction proceeds but, for example,ethers, aromatic hydrocarbons, aliphatic hydrocarbons, amides,halogenated hydrocarbons, nitriles, sulfoxides, organic acids, aromaticamines or a mixture of two or more of them and the like are used.

A reaction temperature is usually about −20 to about 150° C., preferablyabout 0 to about 100° C. A reaction time is usually about 5 minutes toabout 24 hours, preferably about 10 minutes to about 5 hours.

Although a product can be used as the reaction solution itself or as acrude product in the next reaction, it can be isolated from the reactionmixture by the conventional method, and can be easily purified by aseparating means such as recrystallization, distillation, chromatographyand the like.

Compound (Ib) can be obtained by condensing Compound (X) with Compound(XI). This reaction is performed in the presence of a base if desired.

An amount of a base to be used is about 0.8 to about 30 moles,preferably about 1 to about 10 moles relative to 1 mole of Compound (X).

As the “base”, for example, there are basic salts such as sodiumcarbonate, potassium carbonate, cesium carbonate and the like, inorganicbases such as sodium hydroxide, potassium hydroxide and the like,aromatic amines such as pyridine, lutidine and the like, tertiary aminessuch as triethylamine, tripropylamine, tributylamine,cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline,N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and thelike, alkali metal hydrides such as sodium hydride, potassium hydrideand the like, metal amides such as sodium amide, lithiumdiisopropylamide, lithium hexamethyldisilazide and the like, metalalkoxides such as sodium methoxide, sodium ethoxide, potassiumtert-butoxide and the like.

It is advantageous that this reaction is performed without a solvent orin the presence of an inert solvent for a reaction. The solvent is notparticularly limited as long as a reaction proceeds but, for example,aliphatic hydrocarbons, aromatic hydrocarbons, ethers or a mixture oftwo or more of them and the like are used.

A reaction temperature is usually about −78 to about 200° C., preferablyabout room temperature to about 170° C. A reaction time is usually about5 minutes to about 72 hours, preferably about 0.5 to about 24 hours.

Although a product can be used as the reaction solution itself or as acrude product in the next reaction, it can be isolated from the reactionmixture by the conventional method, and can be easily purified by aseparating means such as recrystallization, distillation, chromatographyand the like.

Compound (XIII) is obtained from Compound (XII) by a method described inSynthesis, p.p. 877-882, 1996 or Journal of Organic Chemistry, vol. 61,p.p. 4810-4811, 1996.

Compound (XIV) is obtained by treating Compound (XIII) with a base andcondensing the obtained compound with Compound (V).

An amount of a base is about 0.8 to about 5 moles, preferably about 2 toabout 2.5 moles.

As the “base”, for example, alkyllithiums such as n-butyllithium and thelike and metal amides such as sodium amide, lithium diisopropylamide,lithium hexamethyldisilazide and the like are used.

It is advantageous that this reaction is performed without a solvent orin the presence of an inert solvent for a reaction. The solvent is notparticularly limited as long as a reaction proceeds but, for example,aliphatic hydrocarbons, aromatic hydrocarbons, ethers or a mixture oftwo or more of them and the like are used.

A reaction temperature is usually about −78 to about 60° C., preferablyabout −78 to about 20° C. A reaction time is usually about 5 minutes toabout 24 hours, preferably about 0.5 to about 3 hours.

Although a product can be used as the reaction solution itself or as acrude product in the next reaction, it can be isolated from the reactionmixture by the conventional method, and can be easily purified by aseparating means such as recrystallization, distillation, chromatographyand the like.

Compound (XV) can be obtained by treating Compound (XIV) with halogensor a metal halide. This reaction is performed optionally in the presenceof a base or a basic salt.

An amount of halogens or a metal halide to be used is about 1 to about 5moles, preferably about 1 to about 2 moles relative to 1 mole ofCompound (XIV).

As the “halogens”, there are bromine, chlorine, iodine and the like.

As the “metal halide”, there are copper halide such as copper (II)bromide, copper (II) chloride and the like.

An amount of a base to be used is about 1 to about 10 moles, preferablyabout 1 to about 3 moles relative to 1 mole of Compound (XIV).

As the “base”, for example, there are alkali metal such as sodiumhydroxide, potassium hydroxide, lithium hydroxide and the like, basicsalts such as sodium carbonate, potassium carbonate, cesium carbonate,sodium hydrogencarbonate, sodium acetate and the like, aromatic aminessuch as pyridine, lutidine and the like, tertiary amines such astriethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine,4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylpyrrolidine, N-methylmorpholine and the like.

It is advantageous that this reaction is performed without a solvent orin the presence of an inert solvent for a reaction. The solvent is notparticularly limited as long as a reaction proceeds but, for example,ethers, esters, aromatic hydrocarbons, aliphatic hydrocarbons, amides,halogenated hydrocarbons, nitriles, sulfoxides, organic acids, aromaticamines or a mixture of two or more of them and the like are used.

A reaction temperature is usually about −20 to about 150° C., preferablyabout 0 to about 100° C. A reaction time is usually about 5 minutes toabout 24 hours, preferably about 10 minutes to about 5 hours.

Although a product can be used as the reaction solution itself or as acrude product in the next reaction, it can be isolated from the reactionmixture by the conventional method, and can be easily purified by aseparating means such as recrystallization, distillation, chromatographyand the like.

Compound (XVI) can be obtained by condensing Compound (XV) and Compound(VIII). This reaction is performed optionally in the presence of a base.

In Compound (XV), Hal represents halogens.

When Compound (VIII) is commercially available, it can be used as it is,or is obtained by the method known per se or a method according to theknown method, or further by a method shown by the following reactionformula 3.

An amount of Compound (VIII) to be used is about 0.5 to about 3 moles,preferably about 0.8 to about 2 moles relative to 1 mole of Compound(XV).

An amount of a base to be used is about 1 to about 30 moles, preferablyabout 1 to about 10 moles relative to 1 mole of Compound (XV).

As the “base”, for example, there are basic salts such as sodiumcarbonate, potassium carbonate, cesium carbonate, sodiumhydrogencarbonate, sodium acetate and the like, aromatic amines such aspyridine, lutidine and the like, tertiary amines such as triethylamine,tripropylamine, tributylamine, cyclohexyldimethylamine,4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylpyrrolidine, N-methylmorpholine and the like.

It is advantageous that this reaction is performed without a solvent orin the presence of an inert solvent for a reaction. The solvent is notparticularly limited as long as a reaction proceeds but, for example,halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons,ethers, amides, alcohols, nitrites or a mixture of two or more of themand the like are used.

A reaction temperature is about −5 to about 200° C., preferably about 5to about 150° C. A reaction time is usually about 5 minutes to about 72hours, preferably about 0.5 to about 30 hours.

Although a product can be used as the reaction solution itself or as acrude product in the next reaction, it can be isolated from the reactionmixture by the conventional method, and can be easily purified by aseparating means such as recrystallization, distillation, chromatographyand the like.

Compound (XVII) is obtained by deprotecting Compound (XVI) using an acidor a base.

An amount of an acid or a base to be used is about 0.1 to about 50moles, preferably about 1 to about 20 moles relative to 1 mole ofCompound (XVI).

As the “acid”, for example, mineral acids such as hydrochloric acid,hydrobromic acid, sulfuric acid and the like, Lewis acids such as borontrichloride, boron tribromide and the like, the use of Lewis acidtogether with thiols or sulfides, organic acids such as trifluoroaceticacid, p-toluenesulfonic acid and the like are used.

As the “base”, for example, metal hydroxides such as sodium hydroxide,potassium hydroxide, barium hydroxide and the like, basic salts such assodium carbonate, potassium carbonate and the like, metal alkoxides suchas sodium methoxide, sodium ethoxide, potassium tert-butoxide and thelike, organic bases such as triethylamine, imidazole, formamidine andthe like are used.

It is advantageous that this reaction is performed without a solvent orin the presence of an inert solvent for a reaction. The solvent is notparticularly limited as long as a reaction proceeds but, for example,alcohols, ethers, aromatic hydrocarbons, aliphatic hydrocarbons,halogenated hydrocarbons, sulfoxides, water or a mixture of two or moreof them and the like are used.

A reaction time is usually about 10 minutes to about 50 hours,preferably about 30 minutes to about 12 hours. A reaction temperature isabout 0 to about 200° C., preferably about 20 to about 120° C.

Compound (Ic) can be obtained by condensing Compound (XVII) withCompound (XVIII) optionally in the presence of a base.

An amount of Compound (XVIII) to be used is about 0.8 to about 5 moles,preferably about 1 to about 3 moles relative to 1 mole of Compound(XVII).

An amount of a base to be used is about 0.1 to about 3 moles, preferablyabout 0.3 to about 1.2 moles relative to 1 mole of Compound (XVII).

As the “base”, for example, there are basic salts such as sodiumcarbonate, potassium carbonate, cesium carbonate, sodium acetate and thelike, inorganic base such as sodium hydroxide, potassium hydroxide andthe like, aromatic amines such as pyridine, lutidine and the like,tertiary amines such as triethylamine, tripropylamine, tributylamine,cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline,N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and thelike, alkali metal hydrides such as sodium hydride, potassium hydrideand the like, metal amides such as sodium amide, lithiumdiisopropylamide, lithium hexamethyldisilazide and the like, metalalkoxides such as sodium methoxide, sodium ethoxide, potassiumtert-butoxide and the like.

It is advantageous that this reaction is performed without a solvent orin the presence of an inert solvent for a reaction. The solvent is notparticularly limited as long as a reaction proceeds but, for example,aliphatic hydrocarbons, aromatic hydrocarbons, ethers or a mixture oftwo or more of them and the like are used.

A reaction temperature is usually about −78 to about 100° C., preferablyabout −78 to about 70° C. A reaction time is usually about 5 minutes toabout 24 hours, preferably about 0.5 to about 20 hours.

Although a product can be used as the reaction solution itself or as acrude product in the next reaction, it can be isolated from the reactionmixture by the conventional method, and can be easily purified by aseparating means such as recrystallization, distillation, chromatographyand the like. Thereafter, compounds wherein R⁴ is other than hydrogenatom can be synthesized by performing alkylation or acylation ifdesired.

Compound (XX) is obtained by condensing Compound (XIX) and aminesrepresented by the formula R⁶H.

R⁶ represents “amino optionally having substituents” represented by theabove-mentioned R¹.

In Compound (XIX), R⁵ represents an alkoxy group. As the “alkoxy group”,for example, there are a C₁₋₆ alkoxy group such as methoxy, ethoxy,propoxy, isopropoxy, butoxy and the like.

An amount of the “amines” to be used is about 1 to about 30 moles,preferably about 1 to about 10 moles relative to 1 mole of Compound(XIX).

It is advantageous that this reaction is performed without a solvent orin the presence of an inert solvent for a reaction. The solvent is notparticularly limited as long as a reaction proceeds but, for example,halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons,ethers, amides, alcohols, nitriles, ketones or a mixture of two or moreof them and the like are used.

A reaction temperature is about −5 to about 200° C., preferably about 5to about 120° C. A reaction time is usually about 5 minutes to about 72hours, preferably about 0.5 to about 30 hours.

Although a product can be used as the reaction solution itself or as acrude product in the next reaction, it can be isolated from the reactionmixture by the conventional method, and can be easily purified by aseparating means such as recrystallization, distillation, chromatographyand the like.

Compound (VIII) is obtained by hydrolysing Compound (XX) using an acidor a base.

An amount of an acid or a base to be used is about 0.1 to about 50moles, preferably about 1 to about 20 moles relative to 1 mole ofCompound (XX), respectively.

As the “acid”, for example, mineral acids such as hydrochloric acid,hydrobromic acid, sulfuric acid and the like, Lewis acids such as borontrichloride, boron tribromide and the like, the use of Lewis acidtogether with thiols or sulfides, organic acids such as trifluoroaceticacid, p-toluenesulfonic acid and the like are used.

As the “base”, for example, metal hydroxides such as sodium hydroxide,potassium hydroxide, barium hydroxide and the like, basic salts such assodium carbonate, potassium carbonate, sodium acetate and the like,metal alkoxides such as sodium methoxide, sodium ethoxide, potassiumtert-butoxide and the like, organic bases such as triethylamine,imidazole, formamidine and the like are used.

It is advantageous that this reaction is performed without a solvent orin the presence of an inert solvent for a reaction. The solvent is notparticularly limited as long as a reaction proceeds but, for example,alcohols, ethers, aromatic hydrocarbons, aliphatic hydrocarbons,halogenated hydrocarbons, sulfoxides, water or a mixture of two or moreof them and the like are used.

A reaction time is usually about 10 minutes to about 50 hours,preferably about 30 minutes to about 12 hours. A reaction temperature isabout 0 to about 200° C., preferably about 20 to about 120° C.

Compound (VIII) can be obtained by treating Compound (XXI) with hydrogensulfide in the presence of a base.

An amount of hydrogen sulfide is about 1 mole to about 30 moles relativeto 1 mole of Compound (XXI).

An amount of a base to be used is about 1 to about 30 moles, preferablyabout 1 to about 10 moles relative to 1 mole of Compound (XXI).

As the “base”, for example, there are aromatic amines such as pyridine,lutidine and the like, tertiary amines such as triethylamine,tripropylamine, tributylamine, cyclohexyldimethylamine,4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylpyrrolidine, N-methylmorpholine and the like, ammonia and thelike.

It is advantageous that this reaction is performed without a solvent orin the presence of an inert solvent for a reaction. The solvent is notparticularly limited as long as a reaction proceeds but, for example,halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons,ethers, aromatic amines or a mixture of two or more of them and the likeare used.

This reaction is performed under atmospheric pressure or underpressurized condition. A reaction temperature is usually about −20 toabout 80° C., preferably about −10 to about 30° C. A reaction time isusually about 5 minutes to about 72 hours, preferably about 0.5 to about30 hours.

Although a product can be used as the reaction solution itself or as acrude product in the next reaction, it can be isolated from the reactionmixture by the conventional method, and can be easily purified by aseparating means such as recrystallization, distillation, chromatographyand the like.

Compound (VIII) can also be obtained by treating Compound (XXII) withphosphorus pentasulfide or Lawesson's reagent.

An amount of phosphorus pentasulfide or Lawesson's reagent to be used isabout 0.5 to about 10 moles, preferably about 0.5 to about 3 molesrelative to 1 mole of Compound (XXII).

It is advantageous that this reaction is performed without a solvent orin the presence of an inert solvent for a reaction. The solvent is notparticularly limited as long as a reaction proceeds but, for example,ethers, aromatic hydrocarbons, aliphatic hydrocarbons, halogenatedhydrocarbons or a mixture of two or more of them and the like are used.

A reaction time is usually 10 minutes to about 50 hours, preferablyabout 30 minutes to about 12 hours. A reaction temperature is usuallyabout 0 to about 150° C., preferably about 20 to about 120° C.

Although a product (VIII) can be used as the reaction solution itself oras a crude product in the next reaction, it can be isolated from thereaction mixture by the conventional method, and can be easily purifiedby a separating means such as recrystallization, distillation,chromatography and the like.

When Compound (I) (including Compound (Ia), (Ib) and (Ic)) is acylaminocompound, an objective compound can be also obtained by subjecting thecorresponding amine compound to an acylating reaction known per se.

For example, among Compound (I), a compound wherein R¹ is acylaminogroup optionally having substituents is obtained by reacting thecorresponding 2-thiazolamine and an acylating agent optionally in thepresence of a base or an acid.

An amount of an acylating agent to be used is about 1 to about 5 moles,preferably about 1 to about 2 moles relative to 1 mole of thecorresponding 2-thiazolamine.

As the “acylating agent”, for example, there are carboxylic acidscorresponding to an objective acyl group or a reactive derivativethereof (for example, acid halide, acid anhydride, ester and the like)and the like.

An amount of a base or an acid to be used is about 0.8 to about 5 moles,preferable about 1 to about 2 moles relative to 1 mole of thecorresponding 2-thiazolamine.

As the “base”, for example, there are triethylamine, pyridine,4-dimethylaminopyridine and the like.

As the “acid”, for example, there are methanesulfonic acid,p-toluenesulfonic acid, camphorsulfonic acid and the like.

It is advantageous that this reaction is performed without a solvent orin the presence of an inert solvent for a reaction. The solvent is notparticularly limited as long as a reaction proceeds but, for example,ethers, aromatic hydrocarbons, aliphatic hydrocarbons, amides,halogenated hydrocarbons, nitrites, sulfoxides, aromatic amines or amixture of two or more of them and the like are used.

A reaction temperature is about −20 to about 150° C., preferably about 0to about 100° C. A reaction time is usually 5 minutes to about 24 hours,preferably about 10 minutes to about 5 hours.

Although a product can be used as the reaction solution itself or as acrude product in the next reaction, it can be isolated from the reactionmixture by the conventional method, and can be easily purified by aseparating means such as recrystallization, distillation, chromatographyand the like.

Compound (Id) is also obtained by a method shown by the reaction formula4 or a method according that method.

Compound (Id) is obtained by treating Compound (I) with an organicperoxy acid.

An amount of an organic peroxy acid to be used is about 0.8 to about 10moles, preferable about 1 to about 3 moles-relative to 1 mole ofCompound (I).

As the “organic peroxy acid”, for example, there are peracetic acid,trifluoroperacetic acid, m-chloroperbenzoic acid and the like.

It is advantageous that this reaction is performed without a solvent orin the presence of an inert solvent for a reaction. The solvent is notparticularly limited as long as a reaction proceeds but, for example,halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons,organic acids, ethers, amides, sulfoxides, alcohols, nitriles, ketonesor a mixture of two or more of them and the like are used.

A reaction temperature is about −20 to about 130° C., preferably about 0to about 100° C. A reaction time is usually 5 minutes to about 72 hours,preferably about 0.5 to about 12 hours.

Alternatively, Compound (Id) is also obtained by treating Compound (I)with hydrogen peroxide or alkyl hydroperoxide optionally in the presenceof a base, an acid or a metal oxide.

An amount of hydrogen peroxide or alkyl hydroperoxide to be used isabout 0.8 to about 10 moles, preferably about 1 to 3 moles to 1 mole ofCompound (I).

As the “alkyl hydroperoxide”, for example, there are tert-butylhydroperoxide, cumene hydroperoxide and the like.

An amount of a base, an acid or a metal oxide to be used is about 0.1 toabout 30 moles, preferably 0.8 to about 5 moles relative to 1 mole ofCompound (I).

As the “base”, for example, there are inorganic bases such as sodiumhydroxide, potassium hydroxide and the like, basic salts such as sodiumcarbonate, potassium carbonate, sodium acetate and the like.

As the “acid”, for example, there are mineral acids such as hydrochloricacid, sulfuric acid, perchloric acid and the like, Lewis acids such asboron trifluoride, aluminum chloride, titanium tetrachloride and thelike, organic acids such as formic acid, acetic acid and the like.

As the “metal oxide”, for example, there are vanadium oxide (V₂O₅),osmium tetroxide (OsO₄), tungsten oxide (WO₃), molybdenum oxide (MoO₃),selenium dioxide (SeO₂), chromium oxide (CrO₃) and the like.

It is advantageous that this reaction is performed without a solvent orin the presence of an inert solvent for a reaction. The solvent is notparticularly limited as long as a reaction proceeds but, for example,halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons,organic acids, ethers, amides, sulfoxides, alcohols, nitriles, ketonesor a mixture of two or more of them and the like are used.

A reaction temperature is about −20 to about 130° C., preferably about 0to about 100° C. A reaction time is usually 5 minutes to about 72 hours,preferably about 0.5 to about 12 hours.

Although a product can be used as the reaction solution itself or as acrude product in the next reaction, it can be isolated from the reactionmixture by the conventional method, and can be easily purified by aseparating means such as recrystallization, distillation, chromatographyand the like.

Alternatively, Compound (Ic) is also obtained by a method shown by thefollowing reaction formula 5:

Compound (XXIII) is obtained by deprotecting Compound (XIV) using anacid or a base.

An amount of an acid or a base to be used is about 0.1 to about 50moles, preferably about 1 to about 20 moles relative to one mole ofCompound (XIV), respectively.

As the “acid”, for example, mineral acids such as hydrochloric acid,hydrobromic acid, sulfuric acid and the like, Lewis acids such as borontrichloride, boron tribromide and the like, the use of Lewis acidtogether with thiols or sulfides, organic acids such as trifluoroaceticacid, p-toluenesulfonic acid and the like are used.

As the “base”, for example, metal hydroxides such as sodium hydroxide,potassium hydroxide, barium hydroxide and the like, basic salts such assodium carbonate, potassium carbonate and the like, metal alkoxides suchas sodium methoxide, sodium ethoxide, potassium tert-butoxide and thelike, organic bases such as triethylamine, imidazole, formamidine andthe like are used.

It is advantageous that this reaction is performed without a solvent orin the presence of an inert solvent for a reaction. The solvent is notparticularly limited as long as a reaction proceeds but, for example,alcohols, ethers, aromatic hydrocarbons, aliphatic hydrocarbons,halogenated hydrocarbons, sulfoxides, water or a mixture of two or moreof them and the like are used.

A reaction time is usually about 10 minutes to about 50 hours,preferably about 30 minutes to about 12 hours. A reaction temperature isabout 0 to about 200° C., preferably about 20 to about 120° C.

Although a product can be used as the reaction solution itself or as acrude product in the next reaction, it can be isolated from the reactionmixture by the conventional method, and can be easily purified by aseparating means such as recrystallization, distillation, chromatographyand the like.

Compound (XXIV) is obtained by condensing Compound (XXIII) and Compound(XVIII) optionally in the presence of a base.

An amount of Compound (XVIII) to be used is about 0.8 to about 5 moles,preferably about 1 to about 3 moles relative to one mole of Compound(XXIII).

An amount of a base to be used is about 0.1 to about 3 moles, preferablyabout 0.3 to about 1.2 moles relative to 1 mole of Compound (XXIII).

As the “base”, for example, basic salts such as sodium carbonate,potassium carbonate, cesium carbonate, sodium acetate and the like,inorganic bases such as sodium hydroxide, potassium hydroxide and thelike, aromatic amines such as pyridine, lutidine and the like, tertiaryamines such as triethylamine, tripropylamine, tributylamine,cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline,N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and thelike, alkali metal hydrides such as sodium hydride, potassium hydrideand the like, metal amides such as sodium amide, lithiumdiisopropylamide, lithium hexamethyldisilazide and the like, metalalkoxides such as sodium methoxide, sodium ethoxide, potassiumtert-butoxide and the like.

It is advantageous that this reaction is performed without a solvent orin the presence of an inert solvent for a reaction. The solvent is notparticularly limited as long as a reaction proceeds but, for example,aliphatic hydrocarbons, aromatic hydrocarbons, ethers, water or amixture of two or more of them and the like are used.

A reaction temperature is usually about −78 to about 100° C., preferablyabout −78 to about 70° C. A reaction time is usually about 5 minutes toabout 24 hours, preferably about 0.5 to about 20 hours.

Although a product can be used as the reaction solution itself or as acrude product in the next reaction, it can be isolated from the reactionmixture by the conventional method, and can be easily purified by aseparating means such as recrystallization, distillation, chromatographyand the like.

Compound (XXV) is obtained by treating Compound (XXIV) with halogens ora metal halide. This reaction is performed optionally in the presence ofa base or a basic salt.

An amount of halogens or a metal halide to be used is about 1 to about 5moles, preferably about 1 to about 2 moles relative to one mole ofCompound (XXIV).

As the “halogens”, there are bromine, chlorine, iodine and the like.

As the “metal halide”, there are copper halide such as copper (II)bromide, copper (II) chloride and the like.

An amount of a base to be used is about 1 to about 10 moles, preferablyabout 1 to about 3 moles relative to 1 mole of Compound (XXIV).

As the “base”, for example, there are alkali metals such as sodiumhydroxide, potassium hydroxide, lithium hydroxide and the like, basicsalts such as sodium carbonate, potassium carbonate, cesium carbonate,sodium hydrogencarbonate, sodium acetate and the like, aromatic aminessuch as pyridine, lutidine and the like, tertiary amines such astriethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine,4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylpyrrolidine, N-methylmorpholine and the like.

It is advantageous that this reaction is performed without a solvent orin the presence of an inert solvent for a reaction. The solvent is notparticularly limited as long as a reaction proceeds but, for example,ethers, esters, aromatic hydrocarbons, aliphatic hydrocarbons, amides,halogenated hydrocarbons, nitrites, sulfoxides, organic acids, aromaticamines or a mixture of two or more of them and the like are used.

A reaction temperature is usually about −20 to about 150° C., preferablyabout 0 to about 100° C. A reaction time is usually about 5 minutes toabout 24 hours, preferably about 10 minutes to about 5 hours.

Although a product can be used as the reaction solution itself or as acrude product in the next reaction, it can be isolated from the reactionmixture by the conventional method, and can be easily purified by aseparating means such as recrystallization, distillation, chromatographyand the like.

Compound (Ic) is obtained by condensing Compound (XXV) and Compound(VIII). This reaction is performed optionally in the presence of a base.

In Compound (XXV), Hal represents halogens.

An amount of Compound (VIII) to be used is about 0.5 to about 3.0 moles,preferably about 0.8 to about 2 moles relative to 1 mole of Compound(XXV).

An amount of a base to be used is about 1 to about 30 moles, preferablyabout 1 to about 10 moles relative to 1 mole of Compound (XXV).

As the “base”, for example, there are basic salts such as sodiumcarbonate, potassium carbonate, cesium carbonate, sodiumhydrogencarbonate, sodium acetate and the like, aromatic amines such aspyridine, lutidine and the like, tertiary amines such as triethylamine,tripropylamine, tributylamine, cyclohexyldimethylamine,4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylpyrrolidine, N-methylmorpholine and the like.

It is advantageous that this reaction is performed without a solvent orin the presence of an inert solvent for a reaction. The solvent is notparticularly limited as long as a reaction proceeds but, for example,halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons,ethers, amides, alcohols, nitriles or a mixture of two or more of themand the like are used.

A reaction temperature is usually about −5 to about 200° C., preferablyabout 5 to about 150° C. A reaction time is usually about 5 minutes toabout 72 hours, preferably about 0.5 to about 30 hours.

Although a product can be used as the reaction solution itself or as acrude product in the next reaction, it can be isolated from the reactionmixture by the conventional method, and can be easily purified by aseparating means such as recrystallization, distillation, chromatographyand the like. Thereafter, if desired, compounds other than a compoundwherein R⁴ is hydrogen atom may be synthesized by performing alkylationor acylation.

Compound (XXVII) is obtained by treating Compound (XXVI) with a base andcondensing the obtained compound with Compound (V).

In Compound (XXVI), Hal′ represents halogen atoms such as fluorine,chlorine, bromine and iodine.

An amount of a base to be used is about 0.8 to about 5 moles, preferablyabout 1 to about 1.2 moles relative to 1 mole of Compound (XXVI).

As the “base”, for example, alkyllithiums such as n-butyllithium and thelike, metal amides such as sodium amide, lithium diisopropylamide,lithium hexamethyldisilazide and the like are used.

It is advantageous that this reaction is performed without a solvent orin the presence of an inert solvent for a reaction. The solvent is notparticularly limited as long as a reaction proceeds but, for example,aliphatic hydrocarbons, aromatic hydrocarbons, ethers or a mixture oftwo or more of them and the like are used.

A reaction temperature is usually about −78 to about 60° C., preferablyabout −78 to about 20° C. A reaction time is usually about 5 minutes toabout 24 hours, preferably about 0.5 to about 3 hours.

Although a product can be used as the reaction solution itself or as acrude product in the next reaction, it can be isolated from the reactionmixture by the conventional method, and can be easily purified by aseparating means such as recrystallization, distillation, chromatographyand the like.

Compound (XXVIII) is obtained by treating Compound (XXVII) with halogensor a metal halide. This reaction is performed optionally in the presenceof a base or a basic salt.

In Compound (XXVII), Hal′ represents halogens such as fluorine,chlorine, bromine and iodine.

An amount of halogens or a metal halide to be used is about 1 to about 5moles, preferably about 1 to about 2 moles relative to one mole ofCompound (XXVII).

As the “halogens”, there are bromine, chlorine, iodine and the like.

As the “metal halide”, there are copper halide such as copper (II)bromide, copper (II) chloride and the like.

An amount of a base to be used is about 1 to about: 10 moles, preferablyabout 1 to about 3 moles relative to 1 mole of Compound (XXVII).

As the “base”, for example, there are alkali metals such as sodiumhydroxide, potassium hydroxide, lithium hydroxide and the like, basicsalts such as sodium carbonate, potassium carbonate, cesium carbonate,sodium hydrogencarbonate, sodium acetate and the like, aromatic aminessuch as pyridine, lutidine and the like, tertiary amines such astriethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine,4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylpyrrolidine, N-methylmorpholine and the like.

It is advantageous that this reaction is performed without a solvent orin the presence of an inert solvent for a reaction. The solvent is notparticularly limited as long as a reaction proceeds but, for example,ethers, esters, aromatic hydrocarbons, aliphatic hydrocarbons, amides,halogenated hydrocarbons, nitrites, sulfoxides, organic acids, aromaticamines or a mixture of two or more of them and the like are used.

A reaction temperature is usually about −20 to about 150° C., preferablyabout 0 to about 100° C. A reaction time is usually about 5 minutes toabout 24 hours, preferably about 10 minutes to about 5 hours.

Although a product can be used as the reaction solution itself or as acrude product in the next reaction, it can be isolated from the reactionmixture by the conventional method, and can be easily purified by aseparating means such as recrystallization, distillation, chromatographyand the like.

Compound (X) is obtained by condensing Compound (XXVIII) and Compound(VIII). This reaction is performed optionally in the presence of a base.

In Compound (XXVIII), Hal and Hal′ denote halogen atoms such asfluorine, chlorine, bromine and iodine.

An amount of Compound (VIII) to be used is about 0.5 to about 3 moles,preferably about 0.8 to about 2 moles relative to 1 mole of Compound(XXVIII).

An amount of a base to be used is about 1 to about 30 moles, preferablyabout 1 to about 10 moles relative to 1 mole of Compound (XXVIII).

As the “base”, for example, there are basic salts such as sodiumcarbonate, potassium carbonate, cesium carbonate, sodiumhydrogencarbonate, sodium acetate and the like, aromatic amines such aspyridine, lutidine and the like, tertiary amines such as triethylamine,tripropylamine, tributylamine, cyclohexyldimethylamine,4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylpyrrolidine, N-methylmorpholine and the like.

It is advantageous that this reaction is performed without a solvent orin the presence of an inert solvent for a reaction. The solvent is notparticularly limited as long as a reaction proceeds but, for example,halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons,ethers, amides, alcohols, nitriles or a mixture of two or more of themand the like are used.

A reaction temperature is usually about −5 to about 200° C., preferablyabout 5 to about 150° C. A reaction time is usually about 5 minutes toabout 72 hours, preferably about 0.5 to about 30 hours.

Although a product can be used as the reaction solution itself or as acrude product in the next reaction, it can be isolated from the reactionmixture by the conventional method, and can be easily purified by aseparating means such as recrystallization, distillation, chromatographyand the like.

In the above respective reactions, when starting compounds have amino,carboxy, hydroxy as substituents, a protecting groups which aregenerally used in the peptide chemistry or the like may be introducedinto these groups and, after reaction, a desired compound can beobtained by removing protecting groups if needed.

As a protecting group for amino, for example, formyl or C₁₋₆alkyl-carbonyl (for example, acetyl, propionyl and the like),phenylcarbonyl, C₁₋₆ alkoxy-carbonyl (for example, methoxycarbonyl,ethoxycarbonyl and the like), phenyloxycarbonyl, C₇₋₁₀aralkyloxy-carbonyl (for example, benzyloxycarbonyl and the like),trityl, phthaloyl and the like which may have substituents,respectively, are used. As these substituents, halogen atoms (forexample, fluorine, chlorine, bromine, iodine and the like), C₁₋₆alkyl-carbonyl (for example, acetyl, propionyl, valeryl and the like),nitro and the like are used and the number of substituents is 1 to 3.

As a protecting group for carboxy, for example, C₁₋₆ alkyl (for example,methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like),phenyl, trityl, silyl and the like which may have substituents,respectively, are used. As these substituents, halogen atoms (forexample, fluorine, chlorine, bromine, iodine and the like), formyl, C₁₋₆alkyl-carbonyl (for example, acetyl, propionyl, butylcarbonyl and thelike), nitro, C₁₋₆ alkyl (for example, methyl, ethyl, tert-butyl and thelike), C₆₋₁₀ aryl (for example, phenyl, naphthyl and the like) and thelike are used and the number of substituents is 1 to 3.

As a protecting group for hydroxy, for example, C₁₋₆ alkyl (for example,methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like),phenyl, C₇₋₁₁ aralkyl (for example, benzyl and the like), formyl, C₁₋₆alkyl-carbonyl (for example, acetyl, propionyl and the like),phenyloxycarbonyl, C₇₋₁₁ aralkyloxy-carbonyl (for example,benzyloxycarbonyl and the like), tetrahydropyranyl, tetrahydrofuranyl,silyl and the like which may have substituents, respectively, are used.As these substituents, halogen atoms (for example, fluorine, chlorine,bromine, iodine and the like), C₁₋₆ alkyl (for example, methyl, ethyl,tert-butyl and the like), C₇₋₁₁ aralkyl (for example, benzyl and thelike), C₆₋₁₀ aryl (for example, phenyl, naphthyl and the like), nitroand the like are used and the number of substituents is 1 to 4.

In addition, as a method of removing a protecting group, the methodknown per se or a method according to this method is used and, forexample, method by treating with an acid, a base, the ultraviolet ray,hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate,tetrabutylammonium fluoride, palladium acetate and the like or a methodof reduction is used.

In any cases, Compound (I) can be synthesized by further, optionally,performing the known deprotection, acylation, alkylation, hydrogenation,oxidation, reduction, carbon chain extension and substituent exchangereaction alone or in a combination of two or more of them. As thesereactions, the reactions described in Shinjikkenkagakukoza 14, vol. 15,1977 (Maruzen Press) are adopted.

As the above “alcohols”, for example, there are methanol, ethanol,propanol, isopropanol, tert-butanol and the like.

As the above “ethers”, for example, there are diethyl ether, diisopropylether, diphenyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane andthe like.

As the above “halogenated hydrocarbons”, for example, there aredichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachlorideand the like.

As the above “aliphatic hydrocarbons”, for example, there are hexane,pentane, cyclohexane and the like.

As the above “aromatic hydrocarbons”, for example, there are benzene,toluene, xylene, chlorobenzene and the like.

As the above “aromatic amines”, for example, there are pyridine,lutidine, quinoline and the like.

As the above “amides”, for example, there are N,N-dimethylformamide,N,N-dimethylacetamide, hexamethylphosphoric triamide and the like.

As the above “ketones”, for example, there are acetone, methyl ethylketone and the like.

As the above “sulfoxides”, for example, there are dimethyl sulfoxide andthe like.

As the above “nitriles”, for example, acetonitrile, propionitrile andthe like.

As the above “organic acids”, for example, there are acetic acid,propionic acid, trifluoroacetic acid and the like.

When a desired product is obtained in a free form by the above reaction,it may be converted into a salt according to the conventional method or,when a desired product is obtained as a salt, it can be converted into afree form or another salt according to the conventional method. Compound(I) thus obtained can be isolated and purified from the reactionsolution by the known means, for example, trans-solvation,concentration, solvent extraction, fractional distillation,crystallization, recrystallization, chromatography and the like.

When Compound (I), (Ia), (Ib), (Ic) or (Id) is present as aconfigurational isomer, diastereomer, conformer or the like, each can beoptionally isolated by the above separation and purification means. Inaddition, Compound (I), (Ia), (Ib), (Ic) or (Id) is in the form of itsracemate, they can be separated into S- and R-forms by any conventionaloptical resolution.

When Compound (I), (Ia), (Ib), (Ic) or (Id) exists stereoisomer, boththe isomers alone and mixtures of each isomers are included in the scopeof the present invention.

In addition, Compound (I), (Ia), (Ib), (Ic) or (Id) may be hydrated oranhydrated.

Compound (I) may be labeled with an isotope (for example, ³H, ¹⁴C, ³⁵S)or the like.

A prodrug of Compound (I) refers to a compound which is converted intoCompound (I) by an enzyme, gastric acid or the like under thephysiological conditions, that is, a compound which undergoes enzymaticoxidation, reduction, hydrolysis or the like to be converted intoCompound (I), and a compound which undergoes hydrolysis or the like bygastric acid or the like to be converted into Compound (I). As a prodrugof Compound (I), there are a compound in which an amino group ofCompound (I) is acylated, alkylated or phosphorylated (for example, acompound in which an amino group of Compound (I) is eicosanoylation,alanylation, pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofuranylation, pyrrolidinylmethylation, pivaloyloxymethylation,tert-butylation); a compound in which a hydroxy group of Compound (I) isacylated, alkylated, phosphorylated or boronylated (for example, acompound in which a hydroxy group of Compound (I) is acetylated,palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated,alanylated, dimethylaminomethylcarbonylated); a compound in which acarboxy group of Compound (I) is esterified or amidated (a compound inwhich a carboxy group of Compound (I) is ethylesterified,phenylesterified, carboxymethylesterified,dimethylaminomethylesterified, pivaloyloxymethylesterified,ethoxycarbonyloxyethylesterified, phthalidylesterified,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterified,cyclohexyloxycarbonylethylesterified, methylamidated); and the like.These compounds can be prepared from Compound (I) by the method knownper se.

Alternatively, a prodrug of Compound (I) may be a compound which ischanged into Compound (I), (Ia), (Ib), (Ic) or (Id) under thephysiological conditions described in “Iyakuhin no kaihatsu”, publishedby Hirokawashoten in 1990, vol. 7, Melecular Design, pages 163-198.

Compound (I) of the present invention shows the high affinity foradenosine receptor, in particular, A₃ receptor and has the low toxicityand little side effect and, therefore, is useful as a safe drug.

A pharmaceutical composition of the present invention containingCompound (I) shows an excellent adenosine A₃ receptor antagonisticactivity to a mammal (for example, mouse, rat, hamster, rabbit, cat,dog, cow, sheep, monkey, human being and the like) and is also excellentin (oral) absorption, (metabolism) stability and the like and,therefore, can be used as an agent for preventing or treating adenosineA₃ receptor-related diseases, for example, asthma, allergic disease,inflammation, Addison's disease, autoimmune hemolytic anemia, Crohn'sdisease, psoriasis, rheumatism, central nervous disease (for example,cerebrovascular disease such as cerebral hemorrhage, cerebralinfarction, head trauma, spinal trauma, brain edema, multiple sclerosisand the like), neurodegenerative disease (for example, Alzheimer'sdisease, Parkinson's syndrome, amyotrophic lateral sclerosis (ALS)),diabetes and the like. Preferably, Compound (I) is an agent forpreventing or treating central nervous disease, asthma, allergic diseaseand the like.

Compound (I) of the present invention also shows an excellent p38 MAPkinase inhibitory activity and TNF-α inhibitory activity (TNF-αproduction inhibitory activity, TNF-α action inhibitory activity) and isalso useful as a safe drug based these activities.

For example, a pharmaceutical composition of the present inventioncontaining Compound (I) can be used as an agent: for preventing ortreating p38 MAP kinase related diseases and TNF-α related disease, forexample, arthritis (for example, rheumatoid arthritis, osteoarthritis,rheumatoid spondylitis, gouty arthritis, synovitis), toxemia (forexample, sepsis, septic shock, endotoxin shock, Gram-negative sepsis,toxic shock syndrome), inflammatory bowel disease (for example, Crohn'sdisease, ulcerative colitis), inflammatory pulmonary disease (forexample, chronic pneumonia, silicosis, pulmonary sarcoidosis, pulmonarytuberculosis), or cachexia (for example, cachexia derived frominfection, carcinocachexia, cachexia derived from acquiredimmunodeficiency syndrome (AIDS)), arteriosclerosis, Creutzfeldt-Jakobdisease, virus infection (for example, virus infection such ascytomegalovirus, influenza virus, herpesvirus and the like), atopicdermatitis, systemic lupus erythematosus, AIDS encephalopathy,meningitis, angina, cardiac infarction, congestive heart failure,hepatitis, transplantation, dialysis hypotension, disseminatedintravascular coagulation and the like to a mammal (for example, mouse,rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human being and thelike). Preferably, Compound (I) is used as an agent for preventing ortreating rheumatism and the like.

A preparation of the present invention containing Compound (I) has lowtoxicity and can be safely administered orally or parenterally (forexample, locally, rectally or intravenously or the like) as it is or bymixing Compound (I) with a pharmacologically acceptable carrier into,for example, pharmaceutical preparations such as tablet (includingdragee, film coated-tablet and the like), powders, granules, capsules(including soft capsules), solutions, injections, suppositories,sustained releasing preparations and the like according to the methodknown per se normally used in preparation of pharmaceuticalpreparations. A content of Compound (I) in a preparation of the presentinvention is about 0.01 to 100% by weight relative to the wholepreparation. A dose is different depending upon an administrationsubject, route of administration, diseases and the like and thepreparation may be administered, as an adenosine A₃ receptorantagonistic agent, for example, as an oral agent to an asthma patient(weight about 60 kg), about 0.1 to about 30 mg active ingredient(Compound (I))/kg weight per day, preferably about 1 to 20 mg/kg weightper day, once or a few times per day.

As a pharmacologically acceptable carrier which may be used forpreparing a preparation of the present invention, there are theconventional various organic or inorganic carriers as a pharmaceuticalmaterial, for example, excipient, lubricant, binder and disintegratingagent in solid preparations, or solvent, solubilizing agent, suspendingagent, isotonicity, buffer and soothing agent in liquid preparations.Further, if needed, additives such as the conventional preservative,antioxidant, colorant, sweeting agent, adsorbing agent, wetting agentand the like can be appropriately used at an appropriate amount.

As an excipient, for example, there are lactose, sucrose, D-mannitol,starch, corn starch, crystalline cellulose, light silicic acid anhydrideand the like.

As a lubricant, for example, there are magnesium stearate, calciumstearate, talc, colloidal silica and the like.

As a binder, for example, there are crystalline cellulose, sucrose,D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethyl cellulose and the like.

As a disintegrating agent, for example, there are starch, carboxymethylcellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch,L-hydroxypropyl cellulose and the like.

As a solvent, for example, there are water for injection, alcohol,propylene glycol, macrogol, sesame oil, corn oil, olive oil and thelike.

As a solubilizing agent, for example, there are polyethylene glycol,propylene glycol, D-mannitol, benzyl benzoate, ethanol,trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodiumcitrate and the like.

As a suspending agent, for example, there are surfactants such asstearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionate,lecithin, benzalkonium chloride, benzethonium chloride, glycerylmonostearate and the like; hydrophilic polymers such as polyvinylalcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose,hydroxypropyl cellulose and the like.

As an isotonicity, for example, there are glucose, D-sorbitol, sodiumchloride, glycerin, D-mannitol and the like.

As a buffer, for example, there are buffering solutions such asphosphate, acetate, carbonate, citrate and the like.

As a soothing agent, for example, there are benzyl alcohol and the like.

As a preservative, for example, there are p-hydroxybenzoates,chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid,sorbic acid and the like.

As an antioxidant, for example, there are sulfites, ascorbic acid,α-tocopherol and the like.

The present invention will be explained in detail by way of thefollowing Reference Examples, Examples, Preparation Examples and TestExamples but these are more examples and not limit the present inventionand can be varied without departing the scope of the present invention.

“Room temperature” in the following Reference Examples and Examplesindicates normally about 10° C. to about 35° C. “%” indicates percentageby weight unless otherwise indicated, provided that yield representsmol/mol %.

Abbreviations used elsewhere indicate the following meanings:

s: singlet

d: doublet

t: triplet

q: quartet

dd: double doublet

ddd: double double doublet

dt: double triplet

br: broad

J: coupling constant

Hz: Hertz

CDCl₃: deuterated chloroform

¹H-NMR: proton nuclear magnetic resonance spectrum

Me: methyl

EXAMPLES Reference Example 1 2-phenylmethyloxy-4-methylpyridine

Sodium hydride (60% paraffin dispersion, 5.0 g, 120 mmol) was washedwith hexane (5 mL) twice and suspended in tetrahydrofuran (200 mL). Tothis suspension was added dropwise a solution of benzyl alcohol (14 g,120 mmol) in tetrahydrofuran (50 mL) at 0° C. and then, the mixture wasallowed to warm up to room temperature with stirring for 15 minutes. Tothis solution was added a solution of 2-bromo-4-methylpyridine (19.5 mL,110 mmol) in tetrahydrofuran (50 mL) and heated to reflux for 14 hours.To the reaction mixture was added water (200 mL) and extracted withethyl acetate. The extract was dried and the solvent was distilled off.The crude product was distilled under reduced pressure to obtain 13 g ofthe title compound (67 mmol, yield 67%).

Boiling point 116-118° C. (400 Pa)

¹H-NMR (CDCl₃) δ: 2.30 (3H, s), 5.37 (2H, s), 6.63 (1H, s), 6.72 (1H, d,J=5.1 Hz), 7.29-7.50 (5H, m), 8.03 (1H, d, J=5.1 Hz)

Reference Example 2 N-(3,5-dimethylbenzoyl)propyleneimine

3,5-Dimethylbenzoic acid (25 g, 0.17 mol) and N,N-dimethylformamide (0.1mL) were added to thionyl chloride (50 mL) at 0° C. The mixture washeated to reflux for 2 hours. The excess thionyl chloride was distilledoff under reduced pressure and toluene (50 mL) was added to the residue.Toluene was distilled off under reduced pressure to obtain oily3,5-dimethylbenzoyl chloride. A solution of propyleneimine (14 mL, 0.18mol) in tetrahydrofuran (160 mL) was added to 1N aqueous sodiumhydroxide (180 mL). To the solution was added dropwise3,5-dimethylbenzoyl chloride at 0° C. After complete addition, themixture was further stirred for 30 minutes. The reaction mixture wasextracted with ethyl acetate. The extract was dried and the solvent wasdistilled off to obtain 31 g of the title compound (0.16 mol, yield99%).

Oily Product

¹H-NMR (CDCl₃) δ: 1.39 (3H, d, J=5.5 Hz), 2.13 (1H, d, J=3.7 Hz), 2.37(6H, s), 2.47-2.62 (2H, m), 7.19 (1H, s), 7.64 (2H, s)

Reference Example 31-(3,5-dimethylphenyl)-2-(2-phenylmethyloxy-4-pyridyl)ethanone

A solution of diisopropylamine (9.6 mL, 69 mmol) in anhydroustetrahydrofuran (60 mL) was cooled to −50° C. and a solution of 1.6 Mn-butyllithium in hexane (43 mL, 69 mmol) was added dropwise withstirring. After complete addition, the mixture was stirred for10-minutes and subsequently a solution of2-phenylmethyloxy-4-methylpyridine (12 g, 62 mmol) in anhydroustetrahydrofuran (12 mL) at −30° C. After additional stirring for 1 h, asolution of N-(3,5-dimethylbenzoyl)propyleneimine (12 g, 62 mmol) inanhydrous tetrahydrofuran (12 mL) was added at −30° C. After completeaddition, the resulting mixture was allowed to warm up to roomtemperature and the mixture was stirred for 2 hours. Water (60 mL) wasadded to the reaction mixture and extracted with ethyl acetate. Theextract was washed with water, dried and the solvent was distilled off.The residue was purified by silica gel column chromatography(hexane-ethyl acetate, 5:1) to obtain 9.1 g of the title compound (27mmol, yield 44%).

Oily Product

¹H-NMR (CDCl₃) δ: 2.37 (6H, s), 4.20 (2H, s), 5.37 (2H, s), 6.72 (1H,s), 6.81 (1H, d, J=5.1 Hz), 7.22 (1H, s), 7.30-7.49 (5H, m), 7.59 (2H,s), 8.12 (1H, d, J=5.1 Hz)

Reference Example 42-bromo-1-(3,5-dimethylphenyl)-2-(2-phenylmethyloxy-4-pyridyl)ethanonehydrobromide

1-(3,5-Dimethylphenyl)-2-(2-phenylmethyloxy-4-pyridyl)ethanone (3.3 g,10 mmol) was dissolved in acetic acid (10 mL) and bromine (0.51 mL, 10mmol) was added to the solution and stirred at room temperature for 30minutes. The precipitated crude crystals were collected by filtrationand washed with diethyl ether to obtain 4.8 g of the title compound (9.8mmol, yield 98%).

mp. 88-90° C.

Reference Example 5 N-(4-methoxybenzoyl)propyleneimine

A solution of propyleneimine (25 mL, 0.36 mol) in tetrahydrofuran (200mL) was added to 2N aqueous sodium hydroxide (180 mL). To this mixturewas added dropwise a solution of 4-methoxybenzoyl chloride (51 g, 0.30mol) in tetrahydrofuran (100 mL) at 0° C. After complete addition, themixture was stirred further for 30 minutes. The reaction mixture wasextracted with ethyl acetate. The extract was dried and the solvent wasdistilled off to obtain 49 g of the title compound (0.26 mol, yield86%).

Oily Product

¹H-NMR (CDCl₃) δ: 1.39 (3H, d, J=5.6 Hz), 2.11 (1H, d, J=3.0 Hz),2.51-2.57 (2H, m), 3.87 (3H, s), 6.94 (2H, d, J=8.8 Hz), 8.00 (2H, d,J=8.8 Hz)

Reference Example 61-(4-methoxyphenyl)-2-(2-tert-butoxycarbonylamino-4-pyridyl)ethanone

A solution of 2-tert-butoxycarbonylamino-4-methylpyridine (20 g, 97mmol) in anhydrous tetrahydrofuran (300 mL) was cooled to −78° C. and asolution of 1.6 M n-butyllithium in hexane (140 mL, 0.22 mol) was addeddropwise with stirring. After complete addition, the mixture was stirredat room temperature for 30 minutes. And then, the mixture was cooled to−78° C. A solution of N-(4-methoxybenzoyl)propyleneimine in anhydroustetrahydrofuran (50 mL) was added dropwise to the mixture. Aftercomplete addition, the mixture was stirred at room temperature for 2hours. Water (100 mL) and diisopropyl ether (300 mL) were added to thereaction mixture and the resulting crude crystals were collected byfiltration. The crude crystals were recrystallized fromtetrahydrofuran-hexane to obtain 23 g of the title compound (67 mmol,yield 69%).

mp. 187-190° C.

Reference Example 74-[2-amino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]-2-pyridylamine

Bromine (0.68 mL, 13 mmol) was added to a solution of1-(4-methoxyphenyl)-2-(2-tert-butoxycarbonylamino-4-pyridyl)ethanone(4.5 g, 13 mmol) in acetic acid (100 mL) and the mixture was stirred atroom temperature for 30 minutes. The reaction mixture was concentrated.The residue was dissolved in acetonitrile (40 mL) and to the solutionwas added thiourea (1.1 g, 14 mmol) and triethylamine (1.9 mL, 14 mmol)were added and the mixture was stirred at 80° C. for 2 hours. Thereaction mixture was cooled to room temperature and concentrated. Asaturated aqueous sodium hydrogencarbonate (200 mL) was added to theresidue and the resulting solid was collected by filtration and washedwith water. 2N hydrochloric acid (35 mL) was added to the solids and themixture was stirred at 100° C. for 45 minutes. The reaction mixture wascooled to room temperature and, thereafter, 8N aqueous sodium hydroxide(10 mL) and a saturated aqueous solution of sodium hydrogencarbonate(100 mL) were added. The resulting crude crystals were collected byfiltration, and were washed with water. The crude crystals wererecrystallized from ethanol to obtain 2.7 g of the title compound (9.1mmol, yield 69%).

mp. 251-254° C.

Reference Example 8 2-(2-amino-4-pyridyl)-1-(4-methoxyphenyl)ethanone

2N-hydrochloric acid (30 mL) was added to1-(4-methoxyphenyl)-2-(2-tert-butoxycarbonylamino-4-pyridyl)ethanone(6.1 g, 18 mmol) and the mixture was stirred at 100° C. for 2 hours. Thereaction mixture was cooled to room temperature and, thereafter,8N-aqueous sodium hydroxide (10 mL) was added. The resulting crudecrystals were filtered and washed with water. The crude crystals wererecrystallized from tetrahydrofuran-hexane to obtain 4.0 g of the titlecompound (16 mmol, yield 92%).

mp. 170-174° C.

Reference Example 92-(2-benzoylamino-4-pyridyl)-1-(4-methoxyphenyl)ethanone

Benzoyl chloride (4.4 g, 31 mmol) and 4-dimethylaminopyridine (0.57 g,4.7 mmol) were added to a solution of2-(2-amino-4-pyridyl)-1-(4-methoxyphenyl)ethanone (3.8 g, 16 mmol) inN,N-dimethylacetamide (80 mL) and the mixture was stirred at 70° C. for12 hours. After the reaction mixture was cooled to room temperature,water (50 mL) was added. The mixture was extracted with ethyl acetateand the organic layer was washed with a saturated aqueous solution ofsodium chloride. The layer was dried over magnesium sulfate, filteredand concentrated. The residue was dissolved in tetrahydrofuran (80 mL)and methanol (20 mL) and 1N-aqueous solution of sodium hydroxide (50 mL)was added. The mixture was stirred at room temperature for 3 hours. Thereaction mixture was concentrated and water (100 mL) was added. Themixture was extracted with ethyl acetate and the organic layer waswashed with a saturated aqueous solution of sodium chloride. The layerwas dried over magnesium sulfate, filtered and concentrated. The residuewas recrystallized from ethyl acetate-hexane to obtain 3.1 g of thetitle compound (8.9 mmol, yield 57%).

mp. 136-139° C.

Reference Example 101-(3,5-dimethylphenyl)-2-(2-tert-butoxycarbonylamino-4-pyridyl)ethanone

A solution of 2-tert-butoxycarbonylamino-4-methylpyridine (17 g, 82mmol) in anhydrous tetrahydrofuran (250 mL) was cooled to −78° C. and a1.6N solution of n-butyllithium in hexane (120 mL, 0.19 mol) was addeddropwise with stirring. After complete addition, the mixture was stirredat 0° C. for 30 minutes and cooled to −78° C. A solution ofN-(3,5-dimethylbenzoyl)propyleneimine (21 g, 0.11 mol) in anhydroustetrahydrofuran (50 mL) was added dropwise to the mixture. Aftercomplete addition, the mixture was stirred at room temperature for 2hours. Water (100 mL) was added to the reaction mixture and extractedwith ethyl acetate. The organic layer was washed with a saturatedaqueous solution of sodium chloride, dried over magnesium sulfate,filtered and concentrated. The residue was recrystallized fromtetrahydrofuran-hexane to obtain 13 g of the title compound (37 mmol,yield 46%).

mp. 133-136° C.

Reference Example 112-(2-amino-4-pyridyl)-1-(3,5-dimethylphenyl)ethanone

2N-hydrochloric acid (50 mL) was added to1-(3,5-dimethylphenyl)-2-(2-tert-butoxycarbonylamino-4-pyridyl)ethanone(12 g, 36 mmol) and the mixture was stirred at 100° C. for 1 hour. Afterthe reaction mixture was cooled to room temperature, an 8N aqueoussolution of sodium hydroxide (15 mL) was added and extracted with ethylacetate. The organic layer was washed with a saturated aqueous solutionof sodium chloride, dried over magnesium sulfate, filtered andconcentrated. The residue was recrystallized from ethyl acetate toobtain 6.8 g of the title compound (28 mmol, yield 77%).

mp. 123-126° C.

Reference Example 122-(2-benzoylamino-4-pyridyl)-1-(3,5-dimethylphenyl)ethanone

Benzoyl chloride (7.5 g, 53 mmol) and 4-dimethylaminopyridine (1.0 g,8.3 mmol) were added to a solution of2-(2-amino-4-pyridyl)-1-(3,5-dimethylphenyl)ethanone (6.4 g, 27 mmol) inN,N-dimethylacetamide (100 mL) and the mixture was stirred at 70° C. for12 hours. After the reaction mixture was cooled to room temperature,water (50 mL) was added. The mixture was extracted with ethyl acetate.The organic layer was washed with a saturated aqueous solution of sodiumchloride. The layer was dried over magnesium sulfate, filtered andconcentrated. The residue was dissolved in a mixed solvent oftetrahydrofuran (150 mL) and methanol (40 mL) and 1N aqueous solution ofsodium hydroxide (50 mL) was added. The mixture was stirred at roomtemperature for 3 hours. The reaction mixture was concentrated, water(100 mL) was added and neutralized with 2N-hydrochloric acid and asaturated aqueous solution of sodium hydrogencarbonate. The mixture wasextracted with ethyl acetate and the organic layer was washed with asaturated aqueous solution of sodium chloride. The layer was dried overmagnesium sulfate, filtered and concentrated. The residue was purifiedby silica gel column chromatography (hexane-ethyl acetate, 2:1) toobtain 6.4 g of the title compound (19 mmol, yield 70%).

Oily Product

¹H-NMR (CDCl₃) δ: 2.39 (6H, s), 4.33 (2H, s), 6.98-7.01 (1H, m), 7.23(1H, s), 7.45-7.58 (3H, m), 7.63 (2H, s), 7.89-7.94 (2H, m), 8.21 (1H,d, J=5.2 Hz), 8.36 (1H, s), 8.71 (1H, br)

Reference Example 13

According to Reference Example 5 and using 3-methylbenzoyl chloride and3-methoxybenzoyl chloride, respectively, instead of 4-methoxybenzoylchloride, the following Reference Example compounds 13-1 and 13-2 weresynthesized.

Reference Example Compound 13-1 N-(3-methylbenzoyl)propyleneimine

Oily Product

¹H-NMR (CDCl₃) δ: 1.39 (3H, d, J=5.5 Hz), 2.14 (1H, d, J=3.3 Hz), 2.41(3H, s), 2.51-2.66 (2H, m), 7.32-7.39 (2H, m), 7.79-7.87 (2H, m).

Reference Example Compound 13-2 N-(3-methoxybenzoyl)propyleneimine

Oily Product

¹H-NMR (CDCl₃) δ: 1.40 (3H, d, J=5.9 Hz), 2.14 (1H, d, J=2.9 Hz),2.52-2.65 (2H, m), 3.86 (3H, s), 7.10 (1H, ddd, J=8.4, 2.6, 1.1 Hz),7.37 (1H, dd, J=8.4, 7.3 Hz), 7.55 (1H, dd, J=2.6, 1.5 Hz), 7.63 (1H,ddd, J=7.3, 1.5, 1.1 Hz)

Reference Example 14

According to Reference Example 6 and usingN-(3-methylbenzoyl)propyleneimine instead ofN-(4-methoxybenzoyl)propyleneimine, the following Reference Examplecompound 14 was synthesized.

Reference Example Compound 142-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-methylphenyl)ethanone

mp. 144-146° C.

Reference Example 15 4-(methylthio)thiobenzamide

4-Methylthiobenzonitrile (12 g) was dissolved in a 4N solution ofhydrogen chloride in ethyl acetate (130 mL). To this solution was addedO,O-diethyl dithiophosphate (15 mL) and the mixture was stirred at roomtemperature for 22 hours. Water (100 mL) was added to the reactionmixture and extracted with ethyl acetate. After the insoluble materialswere filtered off, the filtrate was washed with a saturated aqueoussolution of sodium chloride and dried and, thereafter, the solvent wasdistilled off. The residue was recrystallized from ethyl acetate toobtain 10 g of the title compound (yield 67%)

mp. 176-178° C.

Reference Example 16

According to Reference Example 15 and using 4-fluorobenzonitrile,2-chlorobenzonitrile, butyronitrile and valeronitrile, respectively,instead of 4-methylthiobenzonitrile, the following Reference Examplecompounds 16-1-16-4 were synthesized.

Reference Example Compound 16-1 4-fluorothiobenzamide

mp. 156-157° C.

Reference Example Compound 16-2 2-chlorothiobenzamide

mp. 58-59° C.

Reference Example Compound 16-3 Thiobutyramide

Oily Product

¹H-NMR (CDCl₃) δ: 0.99 (3H, t, J=7.6 Hz), 1.72-1.93 (2H, m), 2.64 (2H,t, J=7.6 Hz), 7.02 (1H, br s), 7.77 (1H, br s)

Reference Example Compound 16-4 Thiovaleramide

Oily Product

¹H-NMR (CDCl₃) δ: 0.94 (3H, t, J=7.3 Hz), 1.31-1.49 (2H, m), 1.68-1.83(2H, m), 2.67 (2H, t, J=7.7 Hz), 6.92 (1H, br s), 7.73 (1H, br s)

Reference Example 174-[2-methyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine

Bromine (1.0 mL, 18 mmol) was added to a solution of2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-methylphenyl)ethanone (6.0g, 18 mmol) in acetic acid (50 mL) and the mixture was stirred at roomtemperature for 30 minutes. The reaction mixture was concentrated. Theresidue was dissolved in N,N-dimethylformamide (50 mL) and to thesolution was added thioacetamide (1.4 g, 19 mmol) and the resultingmixture was stirred at room temperature for 20 hours. To the reactionmixture was added a saturated aqueous solution of sodiumhydrogencarbonate (200 mL) and extracted with ethyl acetate. The extractwas dried and the solvent was distilled off. 2N-hydrochloric acid (30mL) was added to the resulting solid and the mixture was stirred at 100°C. for 1 hour. After the reaction mixture was cooled to roomtemperature, the mixture was basified with a 2N aqueous solution ofsodium hydroxide (200 mL) and a saturated aqueous solution of sodiumhydrogen carbonate. The resulting mixture was extracted with ethylacetate and the extract was washed with water. The extract was dried andconcentrated. The residue was purified by silica gel columnchromatography (ethyl acetate) to obtain 2.8 g of the title compound(yield 54%).

mp. 152-153° C.

Reference Example 18

According to Reference Example 17 and using thiopropionamide and4-(methylthio)thiobenzamide, respectively, instead of thioacetamide, thefollowing Reference Example compounds 18-1 and 18-2 were synthesized.

Reference Example Compound 18-14-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine

mp. 144-146° C.

Reference Example Compound 18-24-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridylamine

mp. 181-183° C.

Reference Example 19

According to Reference Example 17 and using1-(4-methoxyphenyl)-2-(2-tert-butoxycarbonylamino-4-pyridyl)ethanoneinstead of2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-methylphenyl)ethanone, thefollowing Reference Example compound 19 was synthesized.

Reference Example Compound 194-[4-(4-methoxyphenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridylamine

mp. 140-141° C.

Reference Example 20

According to Reference Example 8 and using2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-methylphenyl)ethanoneinstead of1-(4-methoxyphenyl)-2-(2-tert-butoxycarbonylamino-4-pyridyl)ethanone,the following Reference Example compound 20 was synthesized.

Reference Example Compound 202-(2-amino-4-pyridyl)-1-(3-methylphenyl)ethanone

mp. 119-120° C.

Reference Example 212-(2-amino-4-pyridyl)-2-bromo-1-(3-methylphenyl)ethanone hydrobromide

Bromine (3.2 mL, 62 mol) was added to a solution of2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-methylphenyl)ethanone (20g, 61 mmol) in acetic acid (60 mL) and the mixture was stirred at 80° C.for 2 hours. After the reaction mixture was cooled to room temperature,the precipitate was filtered to obtain 19 g (yield 81%) of the titlecompound.

mp. 182-185° C.

Reference Example 22

According to Reference Example 9 and using2-(2-amino-4-pyridyl)-1-(3-methylphenyl)ethanone instead of2-(2-amino-4-pyridyl)-1-(4-methoxyphenyl)ethanone, the followingReference Example compound 22 was synthesized.

Reference Example Compound 22N-[4-[2-(3-methylphenyl)-2-oxoethyl]-2-pyridyl]benzamide

mp. 67-69° C.

Reference Example 234-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine

2-(2-Amino-4-pyridyl)-2-bromo-1-(3-methylphenyl)ethanone hydrobromide(5.0 g, 13 mmol) was dissolved in N,N-dimethylformamide (40 mL), to thesolution was added 4-fluorothiobenzamide (2.1 g, 13 mmol) and themixture was stirred at room temperature for 16 hours. A saturatedaqueous solution of sodium hydrogencarbonate (200 mL) was added to thereaction mixture and the mixture was extracted with ethyl acetate. Theextract was dried and the solvent was distilled off. The residue wasrecrystallized from ethanol to obtain 3.9 g (11 mmol, yield 83%) of thetitle compound.

mp. 160-162° C.

Reference Example 24

According to Reference Example 23 and using 2-chlorothiobenzamide,thiobutyramide and thiovaleramide, respectively, instead of4-fluorothiobenzamide, the following Reference Example compounds24-1-24-3 were synthesized.

Reference Example compound24-1:4-[2-(2-chlorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine

mp. 175-177° C.

Reference Example compound 24-24-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridylamine

mp. 113-115° C.

Reference Example compound 24-34-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine

Oily Product

¹H-NMR (CDCl₃) δ: 0.98 (3H, t, J=7.3 Hz), 1.39-1.59 (2H, m), 1.74-1.92(2H, m), 2.34 (3H, s), 3.04 (2H, t, J=7.4 Hz), 41.14 (2H, br s), 6.44(1H, s), 6.56 (1H, dd, J=5.1, 1.5 Hz), 7.09-7.26 (3H, m), 7.41 (1H, s),7.96 (1H, d, J=5.4 Hz)

Reference Example 25 2-fluoro-4-methylpyridine

The title compound was obtained in the same manner as described inJournal of Medicinal Chemistry, vol. 33, 1667-1675, 1990.

Boiling point 82-86° C. (10 kPa)

Reference Example 26 2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone

A solution of diisopropylamine (44 mL, 0.31 mol) in anhydroustetrahydrofuran (300 mL) was cooled to −78° C. under argon atmosphereand a 1.6M solution of n-butyllithium in hexane (190 mL, 0.31 mol) wasadded dropwise to the solution. After complete addition, the mixture wasstirred for 10 minutes and subsequently a solution of2-fluoro-4-methylpyridine (34.5 g, 0.31 mol) in anhydroustetrahydrofuran (30 mL) was added. The reaction mixture was stirred at−10° C. for 30 minutes. The reaction solution was cooled to −78° C. anda solution of N-(3-methylbenzoyl)propyleneimine (52 g, 0.30 mol) inanhydrous tetrahydrofuran (30 mL) was added dropwise. After completeaddition, the mixture was stirred at room temperature for 2 hours. Water(100 mL) was added to the reaction mixture and the mixture was extractedwith ethyl acetate. The extract was washed with water, dried and thesolvent was distilled off. The residue was recrystallized from isopropylether to obtain 35 g (yield 52%) of the title compound.

mp. 66-67° C.

Reference Example 27

According to Reference Example 26 and usingN-(3-methoxybenzoyl)propyleneimine instead ofN-(3-methylbenzoyl)propyleneimine, the following Reference Examplecompound 27 was synthesized.

Reference Example compound 272-(2-fluoro-4-pyridyl)-1-(3-methoxyphenyl)ethanone

Oily Product

¹H-NMR (CDCl₃) δ: 3.86 (3H, s), 4.31 (2H, s), 6.86 (1H, s), 7.03-7.19(2H, m), 7.31-7.59 (3H, m), 8.18 (1H, d, J=5.6 Hz)

Reference Example 28[5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine

Bromine (1.9 mL, 37 mmol) was added to a solution of2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone (8.5 g, 37 mmol) inacetic acid (50 mL) and the mixture was stirred at room temperature for1 hour. The reaction mixture was concentrated. Triethylamine (5.2 mL, 37mmol) was added to a mixture of this residue and thiourea (3.0 g, 40mmol) in acetonitrile (50 mL) and the mixture was stirred at 80° C. for2 hours. A saturated aqueous solution of sodium hydrogencarbonate (50mL) was added to the reaction mixture and the precipitated solid wascollected by filtration. After the resulting solid was washed withwater, it was dried. The crude crystals were recrystallized from ethanolto obtain 3.7 g (yield 35%) of the title compound.

mp. 214-218° C.

Reference Example 29

According to Reference Example 28 and using2-(2-fluoro-4-pyridyl)-1-(3-methoxyphenyl)ethanone instead of2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone, the followingReference Example compound 29 was synthesized.

Reference Example compound 29[5-(2-fluoro-4-pyridyl)-4-(3-methoxyphenyl)-1,3-thiazol-2-yl]amine

mp. 190-191° C.

Reference Example 305-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazole

Bromine (2.7 mL, 52 mmol) was added to a solution of2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone (12 g, 53 mmol) inacetic acid (90 mL) and the mixture was stirred at room temperature for2 hours. The reaction mixture was concentrated. This residue wasdissolved in N,N-dimethylformamide (60 mL), 4-(methylthio)thiobenzamide(9.6 g, 52 mmol) was added and the mixture was stirred at roomtemperature for 15 hours. A saturated aqueous solution of sodiumhydrogencarbonate (100 mL) was poured into the reaction mixture and themixture was extracted with ethyl acetate. The extract was washed withwater, dried and the solvent was distilled off. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate, 4:1) toobtain 4.7 g (yield 23%) of the title compound.

mp. 97-100° C.

Reference Example 315-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazole

To a solution of5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazole(2.7 g, 6.9 mmol) in N,N-dimethylformamide (60 mL) was addedm-chloroperbenzoic acid (3.3 g, 14 mmol) and the mixture was stirred atroom temperature for 1 hour. An 8N aqueous solution of sodium hydroxidewas added to the reaction mixture and the resulting solid was collectedby filtration. This solid was recrystallized from ethanol to obtain 2.5g (yield 85%) of the title compound.

mp. 196-199° C.

Example 1[4-(3,5-dimethylphenyl)-5-(2-phenylmethyloxy-4-pyridyl)-1,3-thiazol-2-yl]amine

Triethylamine (1.4 mL, 10 mmol) was added dropwise to a solution of2-bromo-1-(3,5-dimethylphenyl)-2-(2-phenylmethyloxy-4-pyridyl)ethanonehydrobromide (4.8 g, 9.8 mmol) and thiourea (0.77 g, 11 mmol) inacetonitrile (40 mL) and the mixture was stirred at room temperature for3 hours. The solvent was removed under reduced pressure, a saturatedaqueous solution of sodium hydrogencarbonate was added to the residueand extracted with ethyl acetate. The organic layer was washed withwater, dried and the solvent was distilled off. The resulting crudecrystals were recrystallized from ethyl acetate to obtain 2.0 g (5.2mmol, yield 53%) of the title compound.

mp. 141-143° C.

Example 2N-[4-[2-benzoylamino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide

Benzoyl chloride (0.59 g, 4.2 mmol) and 4-dimethylaminopyridine (0.05 g,0.4 mmol) were added to a solution of4-[2-amino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]-2-pyridylamine (0.42 g,1.4 mmol) in N,N-dimethylacetamide (10 mL) and the mixture was stirredat 70° C. for 19 hours. After the reaction mixture was cooled to roomtemperature, a saturated aqueous solution of sodium hydrogencarbonate(50 mL) was added. The resulting crude crystals were collected byfiltration and washed with water. The crude crystals were recrystallizedfrom ethanol to obtain 0.26 g (0.51 mmol, yield 37%) of the titlecompound.

mp. 230-233° C.

Example 3N-[4-(4-methoxyphenyl)-5-[2-[(3-pyridylcarbonylamino)]-4-pyridyl]-1,3-thiazol-2-yl]nicotinamide

Nicotinoyl chloride hydrochloride (0.72 g, 4.1 mmol) and4-dimethylaminopyridine (0.05 g, 0.4 mmol) were added to a solution of4-[2-amino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]-2-pyridylamine (0.41 g,1.4 mmol) in N,N-dimethylacetamide (10 mL) and the mixture was stirredat 70° C. for 19 hours. After the reaction mixture was cooled to roomtemperature, a saturated aqueous solution of sodium hydrogencarbonate(50 mL) was added. The resulting crude crystals were collected byfiltration and washed with water. The crude crystals were recrystallizedfrom ethanol to obtain 0.23 g (0.44 mmol, yield 33%) of the titlecompound.

mp. 229-232° C.

Example 4N-[4-[2-amino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide

Bromine (0.11 mL, 2.1 mmol) was added to a solution of2-(2-benzoylamino-4-pyridyl)-1-(4-methoxyphenyl)ethanone (0.72 g, 2.1mmol) in acetic acid (20 mL) at 0° C. and the mixture was stirred atroom temperature for 1 hour. The reaction mixture was concentrated. Theresidue was dissolved in acetonitrile (20 mL), to the solution wereadded thiourea (0.17 g, 2.2 mmol) and triethylamine (0.35 mL, 2.5 mmol)and the mixture was stirred at 80° C. for 5 hours. After the reactionmixture was cooled to room temperature, a saturated aqueous solution ofsodium hydrogencarbonate (200 mL) was added and the resulting solid wasfiltered and washed with water. The resulting crude crystals werecollected by filtration and washed with water. The crude crystals wererecrystallized from ethanol to obtain 0.17 g (0.43 mmol, yield 21%) ofthe title compound.

mp. 221-224° C.

Example 5N-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide

Bromine (1.0 mL, 19 mmol) was added to a solution of2-(2-benzoylamino-4-pyridyl)-1-(3,5-dimethylphenyl)ethanone (6.4 g, 19mmol) in acetic acid (80 mL) at 0° C. and the mixture was stirred atroom temperature for 1 hour. The reaction mixture was concentrated. Theresidue was dissolved in acetonitrile (100 mL), to the solution wereadded thiourea (1.5 g, 19 mmol) and triethylamine (2.8 mL, 20 mmol) andthe mixture was stirred at 80° C. for 3 hours. After the reactionmixture was cooled to room temperature, a saturated aqueous solution ofsodium hydrogencarbonate (200 mL) was added and the resulting solid wascollected by filtration and washed with water. The resulting crudecrystals were collected by filtration and washed with water. The crudecrystals were recrystallized from ethanol to obtain 5.0 g (13 mmol,yield 68%) of the title compound.

mp. 120-123° C.

Example 6N-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzylamine

Aluminum lithium hydride (0.16 g, 4.1 mmol) was added to a suspension ofaluminum chloride (0.55 g, 4.1 mmol) in anhydrous tetrahydrofuran (30mL) and the mixture was stirred at room temperature for 15 minutes. Asolution ofN-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide(0.40 g, 1.0 mmol) in anhydrous tetrahydrofuran (10 mL) was added to themixture and the resulting mixture was heated to reflux for 2 hours.After the reaction mixture was cooled to room temperature, water wasadded and extracted with ethyl acetate. The organic layer was washedwith a saturated aqueous solution of sodium chloride, dried overmagnesium sulfate, filtered and concentrated. The residue wasrecrystallized from ethyl acetate-hexane to obtain 0.20 g (0.51 mmol,yield 51%) of the title compound.

mp. 99-102° C.

Example 7N-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamidehydrochloride

A 10% solution of hydrogen chloride in methanol (10 mL) was added to asuspension ofN-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide(0.45 g, 1.1 mmol) in methanol (30 mL) and the mixture was stirred atroom temperature for 30 minutes. The solvent was distilled off and theresidue was recrystallized from methanol to obtain 0.36 g (0.83 mmol,yield 73%) of the title compound.

mp. 202-207° C.

Example 8N-[4-[2-amino-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzylaminedihydrochloride

A 10% solution of hydrogen chloride in methanol (10 mL) was added to asuspension ofN-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzylamine(0.80 g, 2.1 mmol) in methanol (50 mL) and the mixture was stirred atroom temperature for 5 hours. The solvent was distilled off and theresidue was recrystallized from methanol-ethyl acetate to obtain 0.73 g(1.6 mmol, yield 76%) to obtain the title compound.

mp. 161-163° C.

The structures of the compounds obtained in Examples 1 to 6 are shownbelow:

Example 1

Example 2

Example 3

Example 4

Example 5

Example 6

Example 9N-[5-[2-benzoylamino-4-pyridyl)-4-(3,5-dimethylphenyl)-1,3-thiazol-2-yl]acetamide

Acetyl chloride (0.26 mL, 3.7 mmol) and 4-dimethylaminopyridine (0.09 g,0.76 mmol) were added to a solution ofN-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide(0.96 g, 2.4 mmol) in N,N-dimethylacetamide (20 mL) and the mixture wasstirred at 70° C. for 16 hours. After the reaction mixture was cooled toroom temperature, a saturated aqueous solution of sodiumhydrogencarbonate (50 mL) was added. The resulting crude crystals werecollected by filtration and washed with water. The crude crystals wererecrystallized from ethyl acetate to obtain 0.32 g (yield 30%) of thetitle compound.

mp. 238-241° C.

Example 10

According to Example 9 and usingN-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-benzylamineinstead ofN-[4-[(2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide,the following Example compound 10 was synthesized.

Example Compound 10N-[5-(2-benzylamino-4-pyridyl)-4-(3,5-dimethylphenyl)-1,3-thiazol-2-yl]acetamide

mp. 217-219° C.

Example 11

According to Example 4 and using N-methylthiourea instead of thiourea,the following Example compound II was synthesized.

Example Compound 11N-[4-[4-(4-methoxyphenyl)-2-methylamino-1,3-thiazol-5-yl]-2-pyridyl]benzamide

mp. 237-241° C.

Example 12

According to Example 4 and usingN-[4-[2-(3-methylphenyl)-2-oxoethyl]-2-pyridyl]benzamide instead of2-(2-benzoylamino-4-pyridyl)-1-(4-methoxyphenyl)ethanone, the followingExample compound 12 was synthesized.

Example Compound 12N-[4-[2-amino-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide

mp. 216-217° C.

Example 13N-[4-[4-(4-methoxyphenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide

Bromine (0.18 mL, 3.5 mmol) was added to a solution of2-(2-benzoylamino-4-pyridyl)-1-(4-methoxyphenyl)ethanone (1.2 g, 3.4mmol) in acetic acid (10 mL) and the mixture was stirred at roomtemperature for 30 minutes. The reaction mixture was concentrated. Theresidue was dissolved in N,N-dimethylformamide (20 mL), thioacetamide(0.30 g, 19 mmol) was added to the solution and the mixture was stirredat room temperature for 20 hours. An aqueous saturated solution ofsodium hydrogencarbonate (20 mL) was added to the reaction mixture, theresulting mixture was extracted with ethyl acetate and the extract waswashed with water. The extract was dried and concentrated. The residuewas purified by silica gel column chromatography (hexane:ethyl acetate,1:1) to obtain 0.68 g (yield 50%) of the title compound.

mp. 134-135° C.

Example 14N-[4-[2-[(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide

Phenylacetyl chloride (0.33 mL, 2.5 mmol) and triethylamine

(0.31 mL, 2.2 mmol) were added to a solution of4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine(0.81 g, 2.2 mmol) in tetrahydrofuran (20 mL) and the mixture wasstirred at room temperature for 13 hours. An aqueous saturated solutionof sodium hydrogencarbonate (20 mL) was added to the reaction mixture,the resulting mixture was extracted with ethyl acetate and the extractwas washed with water. This extract was dried and concentrated. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate, 2:1) to obtain 0.86 g (yield 80%) of the title compound.

mp. 187-190° C.

Example 15

According to Example 14 and using4-[4-(4-methoxyphenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridylamine,4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine,4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridylamine,4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine,4-[2-(2-chlorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamineand4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridylamine,respectively, instead of4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine,the following Example compounds 15-1-15-6 were synthesized.

Example Compound 15-1N-[4-[4-(4-methoxyphenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide

mp. 118-120° C.

Example Compound 15-2N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide

mp. 107-108° C.

Example Compound 15-3N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide

mp. 109-111° C.

Example Compound 15-4N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide

mp. 92-93° C.

Example Compound 15-5N-[4-[2-(2-chlorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide

mp. 141-142° C.

Example Compound 15-6N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide

mp. 205-206° C.

Example 16

According to Examples 14 and 15 and using benzoyl chloride,

3-phenylpropionyl chloride, 3-(4-methoxyphenyl)propionyl chloride,3-(4-fluorophenyl)propionyl chloride, 4-phenylbutyryl chloride,5-phenylvaleryl chloride, 2-thiophenecarbonyl chloride and 2-naphthoylchloride, respectively, instead of phenylacetyl chloride, the followingExample compounds 16-1-16-18 were synthesized.

Example Compound 16-1N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide

mp. 113-114° C.

Example Compound 16-2N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide

mp. 126-127° C.

Example Compound 16-3N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-(4-methoxyphenyl)propionamide

mp. 137-138° C.

Example Compound 16-4N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-(4-fluorophenyl)propionamide

mp. 116-117° C.

Example Compound 16-5N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-4-phenylbutyramide

mp. 92-93° C.

Example Compound 16-6N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-5-phenylvaleramide

mp. 86-87° C.

Example Compound 16-7N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide

Amorphous Powder

¹H-NMR (CDCl₃) δ: 1.08 (3H, t, J=7.1 Hz), 1.80-1.99 (2H, m), 2.34 (3H,s), 3.04 (2H, t, J=7.7 Hz), 6.88 (1H, dd, J=5.2, 1.7 Hz), 7.15-7.63 (7H,m), 7.90-7.95 (2H, m), 8.11 (1H, d, J=5.2 Hz), 8.51 (1H, s), 8.61 (1H,br s)

Example Compound 16-8N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide

mp. 103-104° C.

Example Compound 16-9N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide

Amorphous Powder

¹H-NMR (CDCl₃) δ: 0.99 (3H, t, J=7.2 Hz), 1.40-1.60 (2H, m), 1.76-1.93(2H, m), 2.34 (3H, s), 3.06 (2H, t, J=7.7 Hz), 6.88 (1H, dd, J=5.0, 1.7Hz), 7.10-7.26 (3H, m), 7.41 (1H, s), 7.46-7.61 (3H, m), 7.94 (2H, dd,J=8.1, 1.5 Hz), 8.10 (1H, d, J=5.0 Hz), 8.52 (1H, s), 8.71 (1H, br s)

Example Compound 16-10N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide

mp. 77-78° C.

Example Compound 16-11N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide

mp. 126-128° C.

Example Compound 16-12N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide

mp. 169-171° C.

Example Compound 16-13N-[4-[2-(2-chlorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide

mp. 138-140° C.

Example Compound 16-14N-[4-[2-(2-chlorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide

mp. 156-158° C.

Example Compound 16-15N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide

mp. 180-182° C.

Example Compound 16-16N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide

mp. 174-175° C.

Example Compound 16-17N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-2-thiophenecarboxamide

mp. 145-147° C.

Example Compound 16-18N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-2-naphthamidemp. 184-186° C. Example 17N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-methylphenylacetamide

Sodium hydride (60% paraffin dispersion, 58 mg, 1.5 mmol) was added to asolution ofN-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide(0.50 g, 1.2 mmol) in dimethyl sulfoxide (5 mL) and the mixture wasstirred at room temperature for 1 hour. Methyl iodide (0.09 mL, 1.5mmol) was added to this reaction solution and the mixture was stirred atroom temperature for 1 hour. A 10% aqueous solution of ammonium chloridewas added to the reaction mixture and the mixture was extracted withethyl acetate. The extract was washed with a saturated aqueous solutionof sodium chloride, dried and concentrated. The residue was purified bysilica gel column chromatography (hexane:ethyl acetate, 7:1→4:1) andwashed with hexane to obtain 0.18 g (yield 35%) of the title compound.

mp. 75-76° C.

Example 18

According to Example 17 and usingN-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamideinstead ofN-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide,the following Example compound 18 was synthesized.

Example Compound 18N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-methyl-3-phenylpropionamide

Oily Product

¹H-NMR (CDCl₃) δ: 1.46 (3H, t, J=7.5 Hz), 2.32 (3H, s), 2.51 (2H, t,J=7.9 Hz), 2.93 (2H, t, J=7.9 Hz), 3.10 (2H, q, J=7.5 Hz), 3.22 (3H, s),6.98 (1H, s), 7.03-7.29 (9H, m), 7.37 (1H, s), 8.37 (1H, d, J=3.6 Hz)

Example 19

According to Example 6 and usingN-[4-[4-(4-methoxyphenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide,N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide,N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide,N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide,N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide,N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide,N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide,N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide,N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide,N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide,N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide,N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide,N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide,N-[4-[2-(2-chlorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide,N-[4-[2-(2-chlorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide,N-[4-[2-(2-chlorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide,N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide,N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide,N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamideandN-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-2-naphthamide,respectively, instead ofN-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide,the following Example compounds 19-1-19-20 were synthesized.

Example Compound 19-1N-benzyl-N-[4-[4-(4-methoxyphenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]amine

mp. 132-133° C.

Example Compound 19-2N-benzyl-N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine

mp. 106-107° C.

Example Compound 19-3N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine

mp. 97-98° C.

Example Compound 19-4N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine

mp. 52-53° C.

Example Compound 19-5N-benzyl-N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]amine

Oily Product

¹H-NMR (CDCl₃) δ: 1.06 (3H, t, J=7.4 Hz), 1.77-1.96 (2H, m), 2.33 (3H,s), 3.00 (2H, t, J=7.7 Hz), 4.38 (2H, d, J=5.4 Hz), 4.83 (1H, br t),6.32 (1H, s), 6.53 (1H, dd, J=5.4, 1.6 Hz), 7.10-7.40 (9H, m), 8.01 (1H,d, J=5.4 Hz)

Example Compound 19-6N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine

Oily Product

¹H-NMR (CDCl₃) δ: 1.08 (3H, t, J=7.5 Hz), 1.78-1.93 (2H, m), 2.32 (3H,s), 2.81 (2H, t, J=7.0 Hz), 3.01 (2H, t, J=7.7 Hz), 3.42 (2H, dt, J=6.2,7.0 Hz), 4.52 (1H, br t), 6.30 (1H, s), 6.51 (1H, dd, J=5.2, 1.5 Hz),7.11-7.34 (8H, m), 7.43 (1H, s), 8.00 (1H, d, J=5.2 Hz)

Example Compound 19-7N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine

Oily Product

¹H-NMR (CDCl₃) δ: 1.08 (3H, t, J=7.4 Hz), 1.78-1.93 (4H, m), 2.32 (3H,s), 2.66 (2H, t, J=7.2 Hz), 3.01 (2H, t, J=7.7 Hz), 3.16 (2H, dt, J=6.2,7.2 Hz), 4.52 (1H, br s), 6.26 (1H, s), 6.49 (1H, dd, J=5.2, 1.5 Hz),7.07-7.32 (8H, m), 7.42 (1H, s), 7.98 (1H, d, J=5.2 Hz)

Example Compound 19-8N-benzyl-N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine

Oily Product

¹H-NMR (CDCl₃) δ: 0.97 (3H, t, J=7.3 Hz), 1.38-1.59 (2H, m), 1.73-1.90(2H, m), 2.33 (3H, s), 3.02 (2H, t, J=7.7 Hz), 4.37 (2H, d, J=5.7 Hz),4.83 (1H, t, J=7.3 Hz), 6.31 (1H, s), 6.52 (1H, d, J=5.5 Hz), 7.09-7.43(9H, m), 8.00 (1H, d, J=5.5 Hz)

Example Compound 19-9N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine

Oily Product

¹H-NMR (CDCl₃) δ: 0.98 (3H, t, J=7.3 Hz), 1.39-1.59 (2H, m), 1.74-1.92(2H, m), 2.32 (3H, s), 2.81 (2H, t, J=7.0 Hz), 3.04 (2H, t, J=7.7 Hz),3.41 (2H, dt, J=6.1, 7.0 Hz), 4.55 (1H, t, J=6.1 Hz), 6.30 (1H, s), 6.51(1H, d, J=5.1 Hz), 7.06-7.19 (3H, m), 7.20-7.38 (5H, m), 7.43 (1H, s),7.99 (1H, d, J=5.1 Hz)

Example Compound 19-10N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine

Oily Product

¹H-NMR (CDCl₃) δ: 0.98 (3H, t, J=7.1 Hz), 1.39-1.57 (2H, m), 1.75-1.98(4H, m), 2.32 (3H, s), 2.67 (2H, t, J=7.8 Hz), 3.04 (2H, t, J=7.7 Hz),3.16 (2H, dt, J=5.9, 6.2 Hz), 4.52 (1H, t, J-5.9 Hz), 6.26 (1H, s), 6.49(1H, d, J=5.1 Hz), 7.06-7.38 (8H, m), 7.42 (1H, s), 7.97 (1H, d, J=5.1Hz)

Example Compound 19-11N-benzyl-N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine

mp. 143-146° C.

Example Compound 19-12N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine

mp. 97-98° C.

Example Compound 19-13N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine

mp. 110-112° C.

Example Compound 19-14N-benzyl-N-[4-[2-(2-chlorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine

mp. 84-86° C.

Example Compound 19-15N-[4-[2-(2-chlorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine

mp. 113-114° C.

Example Compound 19-16N-[4-[2-(2-chlorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine

mp. 101-102° C.

Example Compound 19-17N-benzyl-N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine

mp. 134-136° C.

Example Compound 19-18N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine

mp. 137-139° C.

Example Compound 19-19N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine

mp. 106-107° C.

Example Compound 19-20N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-naphthylmethyl)amine

mp. 144-145° C.

Example 20N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide

To a solution ofN-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide(0.50 g, 1.0 mmol) in N,N-dimethylformamide (5 mL) was addedm-chloroperbenzoic acid (0.55 g, 2.2 mmol) and the mixture was stirredat room temperature for 1 hour. An 8N aqueous solution of sodiumhydroxide was added to the reaction mixture and the resulting solid wascollected by filtration. This solid was recrystallized from ethanol toobtain 0.29 g (yield 54%) of the title compound.

mp. 212-214° C.

Example 21

According to Example 20 and usingN-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide,N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide,N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-2-thiophenecarboxamide,N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-2-naphthamide,N-benzyl-N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine,N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amineandN-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-naphthylmethyl)amine,respectively, instead ofN-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide,the following Example compounds 21-1-21-7 were synthesized.

Example Compound 21-1N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide

mp. 244-245° C.

Example Compound 21-2N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide

mp. 236-237° C.

Example Compound 21-3N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-2-thiophenecarboxamide

mp. 199-201° C.

Example Compound 21-4N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-2-naphthamide

mp. 231-233° C.

Example Compound 21-5N-benzyl-N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine

mp. 148-150° C.

Example Compound 21-6N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine

mp. 167-168° C.

Example Compound 21-7N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-naphthylmethyl)aminemp. 167-168° C. Example 22N-[4-[2-amino-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-benzylamine

A mixture of[5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine (0.29g, 1.0 mmol) and benzylamine (1.2 mL, 11 mmol) was stirred at 150° C.for 3 hours. After the reaction mixture was cooled to room temperature,a saturated aqueous solution of sodium hydrogencarbonate (20 mL) wasadded, the resulting mixture was extracted with ethyl acetate andextract was washed with water. This extract was dried and concentrated.The residue was purified by silica gel column chromatography(hexane:ethyl acetate, 1:1) to obtain 0.16 g (yield 41%) of the titlecompound.

mp. 178-179° C.

Example 23

According to Example 22 and using 4-methoxybenzylamine,3-methoxybenzylamine, 2-methoxybenzylamine, 4-chlorobenzylamine,3-chlorobenzylamine, (R)-1-phenylethylamine, (S)-1-phenylethylamine andN-benzyl-N-methylamine instead of benzylamine, the following Examplecompounds 23-1-23-8 were synthesized.

Example Compound 23-1N-[4-[2-amino-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(4-methoxybenzyl)amine

mp. 183-184° C.

Example Compound 23-2N-[4-[2-amino-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-methoxybenzyl)amine

mp. 152-154° C.

Example Compound 23-3N-[4-[2-amino-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-methoxybenzyl)amine

mp. 158-159° C.

Example Compound 23-4N-[4-[2-amino-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(4-chlorobenzyl)amine

mp. 182-183° C.

Example Compound 23-5N-[4-[2-amino-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-chlorobenzyl)amine

mp. 180-181° C.

Example Compound 23-6(R)—N-[4-[2-amino-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(1-phenylethyl)amine

mp. 94-98° C.

Example Compound 23-7(S)—N-[4-[2-amino-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(1-phenylethyl)amine

mp. 93-96° C.

Example Compound 23-8N-[4-[2-amino-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-benzyl-N-methylamine

mp. 138-140° C.

Example 24

According to Example 22 and using[5-(2-fluoro-4-pyridyl)-4-(3-methoxyphenyl)-1,3-thiazol-2-yl]amineinstead of[5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine, thefollowing Example compound 22 was synthesized.

Example Compound 24N-[4-[2-amino-4-(3-methoxyphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-benzylamine

mp. 217-218° C.

Example 25

According to Example 22 and using5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazoleinstead of[5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine, andusing 2-phenylethylamine, 4-fluorobenzylamine, N-benzyl-N-methylamine,N-methyl-2-phenylethylamine and 2-thienylmethylamine, respectively,instead of benzylamine, the following Example compounds 25-1-25-5 weresynthesized.

Example Compound 25-1N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine

mp. 174-176° C.

Example Compound 25-2N-(4-fluorobenzyl)-N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine

mp. 155-158° C.

Example Compound 25-3N-benzyl-N-methyl-N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine

mp. 165-166° C.

Example Compound 25-4N-methyl-N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine

mp. 116-117° C.

Example Compound 25-5N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-thienylmethyl)amine

mp. 107-109° C.

Example 264-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-5-(2-phenylthio-4-pyridyl)-1,3-thiazole

A mixture of5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazole(0.40 g, 0.94 mmol) and thiophenol (1.0 mL, 9.7 mmol) was stirred at150° C. for 10 hours. After the reaction mixture was cooled to roomtemperature, a saturated aqueous solution of sodium hydrogencarbonatewas added, the resulting mixture was extracted with ethyl acetate andwashed with water. This extract was dried and concentrated. The residuewas purified by silica gel column chromatography (hexane:ethyl acetate,1:1) and recrystallized from ethanol to obtain 0.34 g (yield 70%) of thetitle compound.

mp. 116-118° C.

Example 275-(2-benzylthio-4-pyridyl)-4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazole

After sodium hydride (60% paraffin dispersion, 0.13 g, 3.2 mmol) waswashed with hexane twice, it was suspended in N,N-dimethylformamide (15mL). Phenylmethanethiol (0.35 mL, 3.0 mmol) was added to this suspensionand stirred for 10 minutes. A solution of5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazole(0.49 g, 1.2 mmol) in N,N-dimethylformamide (5 mL) was added to thismixture and stirred for 1 hour. An 8N aqueous solution of sodiumhydroxide was added to the reaction mixture, the resulting mixture wasextracted with ethyl acetate, and the extract was washed with water.This extract was dried and concentrated. The residue was purified bysilica gel column chromatography (hexane:ethyl acetate, 2:1) to obtain0.48 g (yield 79%).

mp. 182-185° C.

Example 284-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-5-(2-phenylsulfonyl-4-pyridyl)-1,3-thiazole

To a solution of4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-5-(2-phenylthio-4-pyridyl)-1,3-thiazole(0.48 g, 0.93 mmol) in N,N-dimethylformamide (10 mL) was addedm-chloroperbenzoic acid (0.51 g, 2.4 mmol) and the mixture was stirredat room temperature for 1 hour. An 8N aqueous solution of sodiumhydroxide was added to the reaction mixture and the resulting solid wascollected by filtration. The solid was recrystallized from ethanol toobtain 0.42 g (yield 82%) of the title compound.

mp. 126-128° C.

Compounds prepared in the above Examples 9-28 are shown in table 1 toTable 6.

TABLE 1

Example Compound No. R² Z Y R¹ R³ mp/° C.  9

—CO— —NH— —NHCOMe

238-241 10

—CH₂— —NH— —NHCOMe

217-219 11

—CO— —NH— —NHMe

237-241 12

—CO— —NH— —NH₂

216-217 13

—CO— —NH— —Me

134-135 14

—CH₂CO— —NH—

187-190   15-1

—CH₂CO— —NH— —Me

118-120   15-2

—CH₂CO— —NH— —CH₂Me

107-108   15-3

—CH₂CO— —NH— —(CH₂)₂Me

109-111   15-4

—CH₂CO— —NH— —(CH₂)₃Me

92-93   15-5

—CH₂CO— —NH—

141-142   15-6

—CH₂CO— —NH—

205-206   16-1

—CO— —NH— —CH₂Me

113-114   16-2

—(CH₂)₂CO— —NH— —CH₂Me

126-127

TABLE 2

Example Compound No R² Z Y R¹ R³ mp/° C. 16-3 

—(CH₂)₂CO— —NH— —CH₂Me

137-138 16-4 

—(CH₂)₂CO— —NH— —CH₂Me

116-117 16-5 

—(CH₂)₃CO— —NH— —CH₂Me

92-93 16-6 

—(CH₂)₄CO— —NH— —CH₂Me

86-87 16-7 

—CO— —NH— —(CH₂)₂Me

amorphous 16-8 

—(CH₂)₂CO— —NH— —(CH₂)₂Me

103-104 16-9 

—CO— —NH— —(CH₂)₃Me

amorphous 16-10

—(CH₂)₂CO— —NH— —(CH₂)₃Me

77-78 16-11

—CO— —NH—

126-128 16-12

—(CH₂)₂CO— —NH—

169-171 16-13

—CO— —NH—

138-140 16-14

—(CH₂)₂CO— —NH—

156-158 16-15

—CO— —NH—

180-182 16-16

—(CH₂)₂CO— —NH—

174-175

TABLE 3

Example Compound No R² Z Y R¹ R³ mp/° C.  16-17

—CO— —NH—

145-147  16-18

—CO— —NH—

184-186 17  

—CH₂CO— —NMe— —CH₂Me

75-76 18  

—(CH₂)₂CO— —NMe— —CH₂Me

oil 19-1

—CH₂— —NH— —Me

132-133 19-2

—CH₂— —NH— —CH₂Me

106-107 19-3

—(CH₂)₂— —NH— —CH₂Me

97-98 19-4

—(CH₂)₃— —NH— —CH₂Me

52-53 19-5

—CH₂— —NH— —(CH₂)₂Me

oil 19-6

—(CH₂)₂— —NH— —(CH₂)₂Me

oil 19-7

—(CH₂)₃— —NH— —(CH₂)₂Me

oil 19-8

—CH₂— —NH— —(CH₂)₃Me

oil 19-9

—(CH₂)₂— —NH— —(CH₂)₃Me

oil

TABLE 4

Example Compound No R² Z Y R¹ R³ mp/° C. 19-10

—(CH₂)₃— —NH— —(CH₂)₃Me

oil 19-11

—CH₂— —NH—

143-146 19-12

—(CH₂)₂— —NH—

97-98 19-13

—(CH₂)₃— —NH—

110-112 19-14

—CH₂— —NH—

84-86 19-15

—(CH₂)₂— —NH—

113-114 19-16

—(CH₂)₃— —NH—

101-102 19-17

—CH₂— —NH—

134-136 19-18

—(CH₂)₂— —NH—

137-139 19-19

—(CH₂)₃— —NH—

106-107 19-20

—CH₂— —NH—

144-145 20  

—CO— —NH—

212-214

TABLE 5

Example Compound No R² Z Y R¹ R³ mp/° C. 21-1

—CH₂CO— —NH—

244-245 21-2

—(CH₂)₂CO— —NH—

236-237 21-3

—CO— —NH—

199-201 21-4

—CO— —NH—

231-233 21-5

—CH₂— —NH—

148-150 21-6

—(CH₂)₃— —NH—

167-168 21-7

—CH₂— —NH—

167-168 22  

—CH₂— —NH— —NH₂

178-179 23-1

—CH₂— —NH— —NH₂

183-184 23-2

—CH₂— —NH— —NH₂

152-154 23-3

—CH₂— —NH— —NH₂

158-159 23-4

—CH₂— —NH— —NH₂

182-183 23-5

—CH₂— —NH— —NH₂

180-181 23-6

—CHMe— (R) —NH— —NH₂

94-98

TABLE 6

Example Compound No R² Z Y R¹ R³ mp/° C. 23-7

—CHMe— (S) —NH— —NH₂

93-96 23-8

—CH₂— —NMe— —NH₂

138-140 24

—CH₂— —NH— —NH₂

217-218 25-1

—(CH₂)₂— —NH—

174-176 25-2

—CH₂— —NH—

155-158 25-3

—CH₂— —NMe—

165-166 25-4

—(CH₂)₂— —NMe—

116-117 25-5

—CH₂— —NH—

107-109 26

— —S—

116-118 27

—CH₂— —S—

182-185 28

— —SO₂—

126-128

Preparation Example 1

(1) Compound of Example 1 50 mg (2) Lactose 34 mg (3) Corn starch 10.6mg (4) Corn starch (pasty) 5 mg (5) Magnesium stearate 0.4 mg (6)Calcium carboxymethylcellulose 20 mg Total 120 mg

According to the conventional method, the above (1) to (6) were mixed,compressed with a compressing machine to obtain tablets.

Preparation Example 2

(1) Example compound 16-1 10.0 mg (2) Lactose 60.0 mg (3) Corn starch35.0 mg (4) Gelatin 3.0 mg (5) Magnesium stearate 2.0 mg

10.0 mg of Example compound 16-1 and a mixture of 60.0 mg of lactose and35.0 mg of corn starch were granulated by passing through a 1 mm meshsieve using 0.03 ml of a 10% aqueous gelatin solution (3.0 mg asgelatin) and, thereafter, dried at 40° C. and re-passed through a sieve.The granules thus obtained were mixed with 2.0 mg of magnesium stearateand compressed. The resulting core tablet is coated with a sugar coatingof a suspension of sucrose, titanium dioxide, talc and arabic gum inwater. The tablet coated with a coating is polished with beeswax toobtain a coated tablet.

Preparation Example 3

(1) Example compound 16-1 10.0 mg (2) Lactose 70.0 mg (3) Corn starch50.0 mg (4) Soluble starch 7.0 mg (5) Magnesium stearate 3.0 mg

After 10.0 mg of Example compound 16-1 and 3.0 mg of magnesium stearateare granulated with 0.07 ml of an aqueous solution of soluble starch(7.0 mg as soluble starch), the granules are dried and mixed with 70.0mg of lactose and 50.0 mg of corn starch. The mixture is compressed toobtain tablets.

Preparation Example 4

(1) Example compound 18 5.0 mg (2) Sodium chloride 20.0 mg (3) Distilledwater to total 2 ml

5.0 mg of Example 18 and 20.0 mg of sodium chloride are dissolved indistilled water and water is added to total 2.0 ml. The solution isfiltered and filled into a 2 ml of ampule under sterile conditions.After the ampule is sterilized, it is sealed to obtain a solution forinjection.

Experimental Example 1

Genetic procedures were according to a method described in MolecularCloning, published by Cold Spring Harbor, Laboratory, 1989 or a methoddescribed in the attached protocol of the reagent.

1) Cloning of Human Adenosine A₃ Receptor

Cloning of an adenosine A₃ receptor gene was performed from human braincDNA by a PCR method. A PCR reaction was performed with a DNA thermalcycler 480 (Perkin Elmer) by using 1 ng of brain cDNA (Toyobo,QUICK-Clone cDNA) as a template, adding each 50 μmol of a primer set5′-CGCCTCTAGACAAGATGCCCAACAACAGCACTGC-3′ (SEQ ID NO:1) and5′-CGGGGTCGACACTACTCAGAATTCTTCTCAATGC-3′ (SEQ ID NO:2) made by referenceto adenosine A₃ receptor gene base sequence reported by Salvatore et al.(Proc. Natl. Acad., Sci. U.S.A., 90:10365-10369, 1993) and employingTakara LA PCR Kit Ver. 2 (Takara Shuzo) (reaction conditions: 35 cyclesof 1 minute at 95° C., 1 minute at 66° C., 2 minutes at 75° C.). Theresulting PCR product was subjected to agarose gel electrophoresis and1.0 kb of DNA fragment was recovered and, thereafter, an adenosine A₃receptor gene was cloned using Original TA Cloning Kit (Funakoshi).

Next, the resulting plasmid was digested with a restriction enzyme XbaI(Takara Shuzo), treated with T4 DNA polymerase (Takara Shuzo) intoend-blunted fragments and further digested with SalI (Takara Shuzo) toobtain adenosine A₃ receptor gene fragments.

2) Preparation of a Plasmid for Expressing of Human Adenosine A₃Receptor

A SRα promoter derived from pTB1411 described in JP-A 5-076385 wasdigested with BglII (Takara Shuzo), blunted, and ligated to EcoRI(Takara Shuzo)-digested pCI vector (Promega) with a DNA Ligation kit(Takara Shuzo) to make pCI-SRα. Next, this pCI-SRα was digested withClaI (Takara Shuzo) and treated with T4 DNA polymerase (Takara Shuzo) toblunt-ended. On the other hand, after pGFP-C1 (Toyobo) was digested withBsu36I (Daiichi Pure Chemicals), treated with T4 DNA polymerase (TakaraShuzo) to blunted end to obtain 1.63 kb of DNA fragment, and both wereligated with a DNA Ligation kit (Takara Shuzo) and competent cells ofEscherichia coli JM109 were transformed to obtain the plasmid pMSRαneo.

Next, after pMSRαneo was digested with EcoRI (Takara Shuzo), treatedwith a T4 DNA polymerase (Takara Shuzo) to blunted end, and furtherdigesting with SalI (Takara Shuzo) to obtain a 5.4 kb DNA fragment. Theobtained DNA fragment and the fragments of adenosine A₃ receptor geneobtained in the above 1) were mixed, ligated with a DNA Ligation kit(Takara Shuzo) and competent cells of Escherichia coli JM109 (TakaraShuzo) were transformed to obtain the plasmid pA₃SRα.

3) Introduction of a Plasmid for Expressing Human Adenosine A₃ Receptorinto CHO (dhfr-) Cells and Expression

CHO (dhfr-) cells obtained by culturing on Ham F12 medium (Nihonseiyaku)containing 10% bovine fetal serum (Lifetec Oriental) in a 750 ml tissueculture flask (Vecton Dickinson) were peeled with 0.5 g/L trypsin-0.2g/L EDTA (Lifetec Oriental) and, thereafter, the cells were washed withPBS (Lifetec Oriental) and centrifuged (1000 rpm, 5 minutes), which wassuspended in PBS.

Next, a DNA was introduced into cells using a gene pulser (BioRad)according to the following conditions. That is, 8×10⁶ cells and 10 μg ofthe plasmid pA₃SRα for expressing human adenosine A₃ receptor were addedto 0.4 cm gapped cuvette and electroporation was performed with 0.8 mlvolume, and under voltage 0.25 kV and capacitance 960 μF. Thereafter,the cells were transferred to Ham F12 medium containing 10% bovine fetalserum, cultured for 24 hours, the cells were peeled again andcentrifuged, then, suspended in Ham F12 medium containing 10% bovinefetal serum to which Geneticin (Lifetec Oriental) had been added to 500μg/ml, which was diluted to 10⁴ cells/ml to seed on a 96-well plate(Becton Dickinson) to obtain Geneticin-resistant strain.

Next, the resulting Geneticin-resistant strain was cultured on a 24well-plate (Becton Dickinson) and, thereafter, an adenosine A₃ receptorexpressing cell was selected among the resistant strains. That is, areaction was conducted in an assay buffer I (HBSS (Wako Pure Chemicals)containing 0.1% BSA, 0.25 mM PMSF, 1 μg/ml pepstatin and 20 μg/mlleupeptin) for 1 hour, washed with an assay buffer I, the radioactivitywas measured with a γ-counter to select a cell to which a ligand isspecifically bound, A₃Ar/CHO strain.

4) Preparation of a Cell Membrane Fraction of a Cell for ExpressingAdenosine A₃ Receptor

After the A₃AR/CHO strain obtained in the above 3) was cultured in HamF12 medium containing 10% bovine fetal serum for 2 days, the cells werepeeled with 0.02% EDTA-containing PBS, the cells were recovered bycentrifugation, suspended in an assay buffer II (50 mM Tris-hydrochloricacid (pH 7.5), 1 mM EDTA, 10 mM magnesium chloride, 0.25 mM PMSF, 1μg/mL pepstatin, 20 μg/ml leupeptin), and the cells were lysed bytreating three times with a polytron homogenizer (Model PT-3000,KINEMATICA AG) at 20,000 rpm for 20 seconds. After the cells wereground, they were centrifuged at 20,000 rpm for 10 minutes to obtain thesupernatant containing the membrane fraction. This supernatant wascentrifuged with a supercentrifuge (Model L8-70M, rotor 70Ti, Beckmann)at 30,000 rpm for 1 hour to obtain the precipitates containing themembrane fraction.

Next, the precipitates were suspended in an assay buffer II containing 2unit/ml adenosine deaminase (Boehringer Mannheim), treated at 30° C. for30 minutes and, thereafter, centrifuged again as described above toobtain the precipitates containing the membrane fraction.

5) Adenosine A₃ Receptor Binding Test

On a 96 well-microplate, [³H]-NECA (Amersham) as a ligand was added toan assay buffer II containing the 100 μg/ml membrane fraction obtainedin the above 4) and various concentrations of test compounds so that theconcentration of the ligand was 10 nM, followed by reaction at roomtemperature for 1 hour. Then, the membrane fraction was transferred tounifilter GF/C (Packard) by filtering the reaction solution using CellHarvester (Packard) and washed three times with 50 mM cooled Tris buffer(pH 7.5). After the filter was dried, Microscint 0 (Packard) was addedto the filter, the radioactivity was measured with a TopCount (Packard)and the concentration (IC₅₀) of a test compound necessary for decreasingan amount of binding of [³H]-NECA to the membrane fraction by 50% wascalculated with PRISM 2.01 (Graphpad Software).

As the result, the IC₅₀ value of the compound of Example 1 was 11.6 nM.It can be seen that Compound (I) is the excellent affinity for adenosineA₃ receptor.

Experimental Example 2

The genetic manipulations described below were according to a methoddescribed in the book (Maniatis et al., Molecular Cloning, Cold SpringHarbor Laboratory, 1989) or a method described in the protocol attachedto the reagent.

(1) Cloning of Human p38 Map Kinase Gene and Preparation of RecombinantBaculovirus

Cloning of human p38 MAP kinase gene was performed by a PCR method usinga primer setP38-U:5′-ACCACTCGAGATGGACTACAAGGACGACGATGACAAGTCTCAGGAGAGGCCCACGTTCTACC-3′[SEQ ID NO:3] and PAG-L:5′-ACCCGGTACCACCAGGTGCTCAGGACTCCATCTCT-3′ [SEQID NO:4] made by reference to the base sequence of p38 MAP kinase genereported by Han et al. (Science 265 (5173), 808-811 (1994)) andemploying kidney cDNA (Toyobo, QUICK-Clone cDNA) as a template.

A PCR reaction was performed by a Hot Start method using AmpliWax PCRGem 100 (Takara Shuzo). As the lower mixed solution, 2 μL 10×LA PCRBuffer, 3 μL 2.5 mM DNTP solution, each 2.5 μL of 12.5 μM primersolution, and 10 μL sterile distilled water were mixed. As the uppermixed solution, 1 μL human cardiac cDNA (1 ng/mL) as a template, 3 μL10×LA PCR Buffer, 1 μL 2.5 mM DNTP solution, 0.5 μL TaKaRa LA Taq DNApolymerase (Takara Shuzo), and 24.5 μL sterile distilled water weremixed. One AmpliWax PCR Gem 100 (Takara Shuzo) was added to the preparedlower mixed solution to treat at 70° C. for 5 minutes and for 5 minutesin an ice and, thereafter, the upper mixed solution was added to preparea reaction solution for PCR. A tube containing the reaction solution wasset at a thermal cycler (Perkin Elmer), which was treated at 95° C. for2 minutes. Further, after repeating 35 times a cycle of 15 seconds at95° C. and 2 minutes at 68° C., treatment was performed at 72° C. for 8minutes. The resulting PCR product was subjected to agarose gel (1%)electrophoresis, 1.1 kb DNA fragment containing p38 MAP kinase gene wasrecovered from the gel and, thereafter, which was inserted intopT7Blue-T vector (Takara Shuzo) to make the plasmid pHP38.

The 4.8 kb XhoI-KpnI fragment of the plasmid pFASTBAC1 (CIBCOBRL) andthe 1.1 kb XhoI-Kpn fragment of the above plasmid pHP38 were ligated tomake the plasmid pFBHP38.

The plasmid pFBHP38 and BAC-TO-BAC Baculovirus Expression System(GIBCOBRL) were used to prepare the recombinant Baculovirus virusstockBAC-HP38.

(2) Cloning of Human MKK3 Gene and Preparation of RecombinantBaculovirus

Cloning of human MKK3 gene was performed by a PCR method using a primersetMKK-U:5′-ACAAGAATTCATAACATATGGCTCATCATCATCATCATCATTCCAAGCCACCCGCACCCAA-3′[SEQ ID NO:5] and MKK-L: 5′-TCCCGTCTAGACTATGAGTCTTCTCCCAGGAT-3′ [SEQ IDNO:6] made by reference to the base sequence of MKK3 gene reported byDerijard, B. et al., Science 267 (5198), 682-685 (1995) and using kidneycDNA (Toyobo, QUICK-Clone cDNA).

A PCR reaction was performed by a Hot Start method using AmpliWax PCRGem 100 (Takara Shuzo). As the lower mixed solution, 2 μL 10×LA PCRBuffer, 3 μL 2.5 mM dNTP solution, each 2.5 μL of 12.5 μM primersolution, and 10 μL sterile distilled water were mixed. As the uppermixed solution, 1 μL human kidney cDNA (1 ng/mL), 3 μL 10×LA PCR Buffer,1 μL 2.5 mM dNTP solution, 0.5 μL TaKaRa LA taq DNA polymerase (TakaraShuzo) and 24.5 μL sterile distilled water were mixed. One AmpliWax PCRGem 100 (Takara Shuzo) was added to the prepared lower mixed solution totreat at 70° C. for 5 minutes and for 5 minutes in an ice and,thereafter, the upper mixed solution was added to prepare a reactionsolution for PCR. A tube containing the reaction solution was set at athermal cycler (Perkin Elmer), which was treated at 95° C. for 2minutes. Further, after repeating 35 times a cycle of 15 seconds at 95°C. and 2 minutes at 68° C., treatment was performed at 72° C. for 8minutes. The resulting PCR product was subjected to agarose gel (1%)electrophoresis, 1.0 kb DNA fragment containing MKK3 gene was recoveredfrom the gel and, thereafter, which was inserted into pT7Blue-T vector(Takara Shuzo) to make the plasmid pHMKK3.

In order to mutate MKK3 into a constitutive active form (from Ser to Gluat 189 position, from Thr to Glu at position 193), a primer setSER-U:5′-GGCTACTTGGTGGACGAGGTGGCCAAGGAGATGGATGCCGGCTGC-3′ [SEQ ID NO:7]and SER-L:5′-GCAGCCGGCATCCATCTCCTTGGCCACCTCGTCCACCAAGTAGCC-31 [SEQ IDNO:8] was used to introduce a mutation by QuickChange Site-DirectedMutagenesis Kit (Stratagene), to obtain pcaMKK3.

4.8 kb EcoRI-XbaI fragment of the plasmid pFASTBAC1 (CIBCOBRL) and the1.0 kb EcoRI-XbaI fragment of the above plasmid pcaMKK 3 were ligated tomake the plasmid pFBcaMKK3.

The plasmid pFBcaMKK3 and BAC-TO-BAC Baculovirus Expression System(GIBCOBRL) were used to prepare the recombinant Baculovirus virusstockBAC-caMKK3.

(3) Preparation of Active Form p38 MAP Kinase

The Sf-21 cells were seeded on 100 ml Sf-900II SFM medium (GIBCOBRL) to1×10⁶ cells/mL and cultured at 27° C. for 24 hours. After each 0.2 mL ofthe virusstock BAC-HP38 of recombinant Baculovirus and BAC-caMKK3 wereadded, the culturing was further performed for 48 hours. After the cellswere separated from the culturing solution by centrifugation (3000 rpm,10 min), the cells were washed twice with PBS. After the cells weresuspended in 10 ml Lysis buffer (25 mM HEPES (pH 7.5), 1% Triton X, 130mM NaCl, 1 mM EDTA, 1 mM DTT, 25 mM β-glycerophosphate, 20 mM leupeptin,1 mM APMSF, 1 mM Sodium orthovanadate), the cells were lysed by treatingtwice with a homogenizer (POLYTRON) at 20000 rpm for 2 minutes. By usingAnti-FLAG M2 Affinity Gel (Eastman Chemical) from the supernatantobtained by centrifugation (40000 rpm, 45 minutes), active form p38 MAPkinase was purified.

(4) Measurement of the p38 MAP Kinase Inhibitory Activity

2.5 μL of a test compound dissolved in DMSO was added to 37.5 μLreaction solution (25 mM HEPES (pH 7.5), 10 mM Magnesium Acetate)containing 260 ng active form p38 MAP kinase and 1 μg Myelin BasicProtein, which was maintained at 30° C. for 5 minutes. The reaction wasinitiated by adding 10 μL ATP solution (2.5 μM ATP, 0.1 μCi [g-³²P]ATP).After the reaction was performed at 30° C. for 60 minutes, the reactionwas stopped by adding 50 μL 20% TCA solution. After the reactionsolution was allowed to stand at 0° C. for 20 minutes, an acid insolublefraction was transferred to GF/C filter (Packard Japan) using CellHarvester (Packard Japan) and washed with 250 mM H₃PO₄. After drying at45° C. for 60 minutes, 40 μM Microscint 0 (Packard Japan) was added andthe radioactivity was measured with a TopCount (Packard Japan). Theconcentration (IC₅₀ value) necessary for inhibiting uptake of ³²P intoan acid insoluble fraction by 50% was calculated with PRISM 2.01(Graphpad Software).

The results are shown in Table 7.

TABLE 7 Example No. IC₅₀ (μM) 1 0.43 2 0.063 3 0.023 4 0.020 5 0.029 60.023

From this, it can be seen that Compound (I) has the p38 MAP kinaseinhibitory activity.

Experimental Example 3 Measurement of Inhibiting Activity of TNF-αProduction

After THP-1 cells which had been cultured on PRMI 1640 medium(manufactured by Life Technologies, Inc.) containing 1% non-activatedbovine fetal serum (manufactured by Life Technologies, Inc., U.S.A.) and10 mM HEPES (pH 7.5) seeded on a 96-well plate to 1×10⁵ cells/well, 1 μLtest compound dissolved in DMSO was added to there. After incubation at37° C. for 1 hour in a CO₂ incubator, LPS (Wako Pure Chemicals) wasadded to the final concentration 5 μg/mL. After cultured at 37° C. for 4hours in a CO₂ incubator, the supernatant was obtained bycentrifugation. The concentration of TNF-α in the supernatant wasmeasured with ELISA (R&D System, Quantikine Kit). The concentration(IC₅₀ value) necessary for inhibiting TNF-α production by 50% wascalculated by PRIMS 2.01 (Graphpad Software).

The results are shown in Table 8.

TABLE 8 Example No. IC₅₀ (μM) 3 0.026 4 0.014 5 0.020 6 0.140

From this, it can be seen that Compound (I) has the excellent inhibitoryactivity of TNF-α production.

INDUSTRIAL APPLICABILITY

Compound (I) or a salt thereof has the excellent adenosine A₃ receptorantagonism and can be used as an agent for preventing or treatingadenosine A₃ receptor related diseases. Further, Compound (I) or a saltthereof shows the excellent p38 MAP kinase inhibiting activity and TNF-αinhibiting activity, and can be also used as an agent for preventing ortreating p38 MAP kinase related diseases and TNF-α related diseases.

1. An optionally N-oxidized compound represented by the formula:

wherein R¹ represents (i) a hydrogen atom, (ii) a C₁₋₆ alkyl group, aC₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a C₃₋₆ cycloalkyl group, aC₆₋₁₄ aryl group or a C₇₋₁₆ aralkyl group [wherein these groups may havesubstituents selected from the group (substituent group A) consisting ofoxo, halogen atom, C₁₋₃ alkylenedioxy, nitro, cyano, optionallyhalogenated C₁₋₆ alkyl, optionally halogenated C₂₋₆ alkenyl, carboxyC₂₋₆ alkenyl, optionally halogenated C₁₋₆ alkynyl, optionallyhalogenated C₃₋₆ cycloalkyl, C₆₋₁₄ aryl, optionally halogenated C₁₋₈alkoxy, C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkoxy, hydroxy, C₆₋₁₄ aryloxy, C₇₋₁₆aralkyloxy, mercapto, optionally halogenated C₁₋₆ alkylthio, C₆₋₁₄arylthio, C₇₋₁₆ aralkylthio, amino, mono-C₁₋₆ alkylamino, mono-C₆₋₁₄arylamino, di-C₁₋₆ alkylamino di-C₆₋₁₄ arylamino, formyl, carboxy, C₁₋₆alkyl-carbonyl, C₃₋₆ cycloalkyl-carbonyl, C₁₋₆ alkoxy-carbonyl, C₆₋₁₄aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₆₋₁₄ aryloxy-carbonyl, C₇₋₁₆aralkyloxy-carbonyl, carbamoyl, thiocarbamoyl, mono-C₁₋₆alkyl-carbamoyl, di-C₁₋₆ alkyl-carbamoyl, C₆₋₁₄ aryl-carbamoyl, C₁₋₆alkylsulfonyl, C₆₋₁₄ arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄arylsulfinyl, formylamino, C₁₋₆ alkyl-carbonylamino, C₆₋₁₄aryl-carbonylamino, C₁₋₆ alkoxy-carbonylamino, C₁₋₆ alkylsulfonylamino,C₆₋₁₄ arylsulfonylamino, C₁₋₆ alkyl-carbonyloxy, C₆₋₁₄ aryl-carbonyloxy,C₁₋₆ alkoxy-carbonyloxy, mono-C₁₋₆ alkyl-carbamoyloxy, di-C₁₋₆alkyl-carbamoyloxy, C₆₋₁₄ aryl-carbamoyloxy, sulfo, sulfamoyl,sulfinamoyl and sulfinamoyl], (iii) an acyl group represented by theformula:—(C═O)—R⁵,—(C═O)—OR⁵, —(C═O)—NR⁵R⁶, —(C═S)—NHR⁵ or —SO₂—R⁷ wherein R⁵represents {circle around (1)} a hydrogen atom or {circle around (2)} aC₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a C₃₋₆cycloalkyl group, a C₆₋₁₄ aryl group or a C₇₋₁₆ aralkyl group optionallyhaving substituents selected from the substituent group A, R⁶ representsa hydrogen atom or a C₁₋₆ alkyl group, R⁷ represents a C₁₋₆ alkyl group,a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a C₃₋₆cycloalkyl group, aC₆₋₁₄ aryl group or a C₇₋₁₆ aralkyl group optionally having substituentsselected from the substituent group A, or (iv) an amino group optionallyhaving substituents selected from the group consisting of {circle around(1)} a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, aC₃₋₆ cycloalkyl group, a C₆₋₁₄ aryl group or a C₇₋₁₆ aralkyl groupoptionally having substituents selected from the substituent group A,{circle around (2)} an acyl group as defined in the (iii), and {circlearound (3)} a C₁₋₆ alkylidene group optionally having substituentsselected from the substituent group A, R² represents a 5 to 10 memberedaromatic heterocyclic group containing 1 to 4 heteroatoms of one or twokinds selected from the group consisting of a nitrogen atom, a sulfuratom and an oxygen atom in addition to carbon atoms, optionally havingsubstituents selected from the substituent group A; R³ represents{circle around (1)} a hydrogen atom or {circle around (2)} a C₆₋₁₄ arylgroup optionally having substituents selected from the substituent groupA; X represents an optionally oxidized sulfur atom, Y represents a bond,an oxygen atom, an optionally oxidized sulfur atom or a grouprepresented by the formula: NR⁴, wherein R⁴ represents {circle around(1)} a hydrogen atom, {circle around (2)} a C₁₋₆ alkyl group, a C₂₋₆alkenyl group, a C₂₋₆ alkynyl group, a C₁₋₆ cycloalkyl group, a C₆₋₁₄aryl group or a C₇₋₁₆ aralkyl group optionally having substituentsselected from the substituent group A or {circle around (3)} an acylgroup as defined in the (iii), and Z represents a bond, a C₁₋₁₅ alkylenegroup, a C₂₋₁₆ alkenylene group or a C₂₋₁₆ alkynylene group optionallyhaving substituents selected from the substituent group A, or a saltthereof.
 2. The compound according to claim 1, wherein Z is a C₁₋₁₅alkylene group, a C₂₋₁₆ alkenylene group or a C₂₋₁₆ alkynylene groupoptionally having substituents selected from the substituent group A. 3.The compound according to claim 1, which is a compound represented bythe formula:

wherein n represents 0 or 1, and other symbols are as defined in claim1, or a salt thereof.
 4. The compound according to claim 1, wherein R¹represents (i) a hydrogen atom, (ii) a C₁₋₆ alkyl group, a C₂₋₆ alkenylgroup, a C₂₋₆ alkynyl group, a C₃₋₆ cycloalkyl group, a C₆₋₁₄ aryl groupor a C₇₋₁₆ aralkyl group [wherein these groups may have substituentsselected from the substituent group A], (iii) an acyl group representedby the formula:—(C═O)—R⁵,—(C═O)—OR⁵, —(C═O)—NR⁵R⁶, —(C═S)—NHR⁵ or —SO₂—R⁷ wherein R⁵represents {circle around (1)} a hydrogen atom or {circle around (2)} aC₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a C₃₋₆cycloalkyl group, a C₆₋₁₄ aryl group or a C₇₋₁₆ aralkyl group optionallyhaving substituents selected from the substituent group A, R⁶ representsa hydrogen atom or a C₁₋₆ alkyl group, R⁷ represents a C₁₋₆ alkyl group,a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a C₃₋₆ cycloalkyl group, aC₆₋₁₄ aryl group or a C₇₋₁₆ aralkyl group optionally having substituentsselected from the substituent group A, or (iv) an amino group, whereinthe amino group may have substituents selected from the group consistingof {circle around (1)} a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆alkynyl group, a C₃₋₆ cycloalkyl group, a C₆₋₁₄ aryl group or a C₇₋₁₆aralkyl group optionally having substituents selected from thesubstituent group A, {circle around (2)} an acyl group as defined in the(iii), and {circle around (3)} a C₁₋₆ alkylidene group optionally havingsubstituents selected from the substituent group A, R² represents a 5 to10 membered aromatic heterocyclic group containing 1 to 4 heteroatoms ofone or two kinds selected from the group consisting of a nitrogen atom,a sulfur atom and an oxygen atom in addition to carbon atoms, optionallyhaving substituents selected from the substituent group A; R³ represents{circle around (1)} a hydrogen atom or {circle around (2)} a C₆₋₁₄monocyclic or fused polycyclic aromatic hydrocarbon group optionallyhaving substituents selected from the substituent group A; X representsS, SO or SO₂; and Y represents a bond, O, S, SO, SO₂ or a grouprepresented by the formula: NR⁴, wherein R⁴ represents {circle around(1)} a hydrogen atom, {circle around (2)} a C₁₋₆ alkyl group, a C₂₋₆alkenyl group, a C₂₋₆ alkynyl group, a C₃₋₆ cycloalkyl group, a C₆₋₁₄aryl or a C₇₋₁₆ aralkyl group optionally having substituents selectedfrom the substituent group A or {circle around (3)} an acyl group asdefined in the (iii).
 5. The compound according to claim 1, wherein R¹is an amino group, as defined in (iv) of claim
 1. 6. The compoundaccording to claim 1, wherein R¹ is (i) a C₁₋₆ alkyl group, (ii) a C₆₋₁₄aryl group optionally substituted with substituents selected from thegroup consisting of C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl and halogen atom,or (iii) an amino group optionally having 1 or 2 acyl represented by theformula: —(C═O)—R⁵′, wherein R⁵′ represents {circle around (1)} a C₁₋₆alkyl group or {circle around (2)} a C₆₋₁₄ aryl group.
 7. The compoundaccording to claim 1, wherein R¹ is an amino group optionally having 1or 2 acyl group represented by —(C═O)—R⁵″, wherein R⁵″ represents aC₆₋₁₄ aryl group.
 8. (canceled)
 9. The compound according to claim 1,wherein R² is a 5 to 10 membered aromatic heterocyclic group containing1 to 4 heteroatoms of one or two kinds selected from the groupconsisting of a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms.
 10. (canceled)
 11. The compound according toclaim 1, wherein R³ is a C₆₋₁₄ aryl group optionally having substituentsselected from the substituent group A.
 12. The compound according toclaim 1, wherein R³ is a C₆₋₁₄ aryl group optionally substituted withone or two C₁₋₆ alkyl or C₁₋₆ alkoxy.
 13. (canceled)
 14. The compoundaccording to claim 1, wherein X is a sulfur atom.
 15. The compoundaccording to claim 1, wherein Y is an oxygen atom or a group representedby the formula: NR⁴, wherein R⁴ is as defined in claim
 1. 16. Thecompound according to claim 1, wherein Y is an oxygen atom, anoptionally oxidized sulfur atom or a group represented by the formula:NR^(4′), wherein R^(4′) represents a C₁₋₆ alkyl group.
 17. The compoundaccording to claim 1, wherein Y is O, NH or S.
 18. The compoundaccording to claim 1, wherein Z is a lower alkylene group optionallyhaving substituents selected from the substituent group A.
 19. Thecompound according to claim 1, wherein Z is a bond or a C₁₋₆ alkylenegroup optionally having oxo.
 20. The compound according to claim 1,wherein R¹ is (i) a C₁₋₆ alkyl group, (ii) a C₆₋₁₄ aryl group optionallysubstituted with C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl or halogen atom, or(iii) an amino group optionally having 1 or 2 acyl group represented bythe formula: —(C═O)—R^(5′) wherein R^(5′) represents {circle around (1)}a C₁₋₆ alkyl group or {circle around (2)} a C₆₋₁₄ aryl group; R² is a 5to 10 membered aromatic heterocyclic group containing 1 to 4 heteroatomsof one or two kinds selected from the group consisting of a nitrogenatom, a sulfur atom and an oxygen atom in addition to carbon atoms; R³is a C₆₋₁₄ aryl group optionally substituted with 1 or 2 C₁₋₆ alkyl orC₁₋₆ alkoxy; X is a sulfur atom; Y is an oxygen atom, an optionallyoxidized sulfur atom or a group represented by the formula: NR^(4′),wherein R^(4′) represents a C₁₋₆ alkyl group; and Z is a C₁₋₆ alkylenegroup optionally having oxo or C₁₋₆ alkyl or a bond.
 21. The compoundaccording to claim 1, wherein R¹ is an amino group optionally having 1or 2 acyl represented by —(C═O)—R⁵″, wherein R⁵″ represents a C₆₋₁₄ arylgroup; R² is a 5 to 10 membered aromatic heterocyclic group containing 1to 4 heteroatoms of one or two kinds selected from the group consistingof a nitrogen atom, a sulfur atom and an oxygen atom in addition tocarbon atoms; R³ is a C₆₋₁₄ aryl group optionally substituted with 1 or2 C₁₋₆ alkyl or C₁₋₆ alkoxy; X is a sulfur atom; Y is O, NH or S; and Zis a bond or a C₁₋₆ alkylene group optionally having oxo. 22-24.(canceled)
 25. A pharmaceutical composition which comprises the compoundaccording to claim 1 together with a pharmacologically acceptablecarrier. 26-41. (canceled) 42.N-[4-[4-(3-Methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-2-thiophenecarboxamide,N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-2-thiophenecarboxamide,orN-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-thienylmethyl)amine,or a salt thereof.